bluuebunny/crossref_metadata_2025 huggingface dataset:
Hyperprogressive disease during treatment with immune checkpoint inhibitors in patients with advanced non-small cell lung cancer (NSCLC).
Authors: Ayala de Miguel Pablo , López Gallego Javier , Gorospe García Itziar , Rivera Vargas Pablo René , Posada Restrepo Andrea , Aires Machado Jonathan , Alonso Calderón Rubén , Rodríguez García José Manuel , Ceballos Eduardo , Acero Caballero Alfonso , Illán Varella Andrea , Quintana Cortés Laura , Borrega Garcia Pablo
Published: May 2020

e21664

Background: Hyperprogressive disease (HPD) is a new pattern of progressión during immunotherapy and is described as an acceleration of tumor growth during treatment with immune checkpoint inhibitors (ICI). The rate of HPD in advanced solid tumors remains unknown, but it has been reported in 9% to 29% of patients in two recent series. Our aim was to study prognostic factors of HPD. Methods: We collected data of 104 patients diagnosed of advanced NSCLC and treated with ICI in monotherapy at our institution between December 2015 and December 2019. Several variables as clinical, tumour-related and therapeutical were included in the analysis. The variables were compared by chi-square and Fisher test, then we performed a multivariate logistic regression model to analyse the effects of the covariates, and finally we performed a Kaplan Meier survival analysis. We described HPD as disease progression at first evaluation with an increase in tumor growth rate exceeding 50%, according to Gustave Roussy criteria previously reported. Results: Cohort of 84 men and 20 women, median age of 67 years and 86% with Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1. 89% were active or ex-smokers and 11% had never smoked. 60% of patients had adenocarcinoma histology, 39% scamous and 1% had not otherwise specified (NOS) carcinoma histology. 3% of patients had III-B stage at the moment of start of immunotherapy, 37% M1a, 30% M1b and 30% M1c. 2 patients had driver mutations in EGFR gene. 41% of patients had unknown PDL1 status; 14% had no PDL1 expression, 14% low expression and 31% high expression. 78% of patients had progressed to prior line of treatment, while 22% were treatment-naive. Nine of 104 patients (8.7%) in our population developed HPD during treatment with ICI. HPD occured within the first two months of treatment in all 9 patients, and was associated with worse overall survival in the multivariate analysis by Cox regression (12.6 vs 2.6 months; HR 13.94, p < 0.001). The presence of 2 or more metastatic sites was related to the development of HPD in the multivariate analysis (HR 8.59, p = 0.026). Conclusions: The incidence of HPD in our population is concordant with previous report about this topic. As previously described by Ferrara et al, HPD was significantly associated with a high number of metastatic sites before start treatment with ICI and correlated with poor outcomes in patients with advanced NSCLC.
Population pharmacokinetic (PK) and exposure-response analyses from the pivotal ALTA-1L study: Model-based analyses supporting the brigatinib dose in patients with anaplastic lymphoma kinase (ALK)–positive non–small cell lung cancer (NSCLC).
Authors: Gupta Neeraj , Reckamp Karen L. , Camidge D. Ross , Kleijn Huub Jan , Ouerdani Aziz , Bellanti Francesco , Maringwa John , Hanley Michael J. , Wang Shining , Zhang Pingkuan , Venkatakrishnan Karthik
Published: May 2020

e21725

Background: Brigatinib is a next-generation ALK tyrosine kinase inhibitor (TKI) with differential activity by dose (90 mg vs 180 mg [with a 7-day lead-in at 90 mg] qd) in the phase 2 post-crizotinib ALTA trial (NCT02094573). Herein, we describe results from population PK and exposure-response analyses of the efficacy and safety of brigatinib 180 mg qd (with a 7-day lead-in at 90 mg) from data in the first-line phase 3 ALTA-1L study (NCT02737501). Methods: Brigatinib plasma concentration-time data were described by a 3-compartment model with transit compartment absorption. Post hoc individual apparent clearance estimates for brigatinib were obtained using Bayesian re-estimation and used to calculate time-averaged area under the concentration-time curve (AUC) values for logistic regression analyses of relationships to response endpoints (confirmed objective response rate [ORR], intracranial ORR) and time-varying AUC values for parametric time-to-event models of relationships to progression-free survival (PFS). Population PK modeling, covariate analysis, and simulations were performed using NONMEM (version 7.3 or higher), running under PsN (Perl-speaks-NONMEM, version 4.6 or higher), while exposure–efficacy and safety analyses were performed using R (version 3.5.2 or higher). Results: Brigatinib PK parameters and estimated systemic exposures for patients in ALTA-1L (ALK TKI–naive setting) were similar to those in the 180 mg qd arm of ALTA. Patient covariates including weight, sex, age, race, and renal function (CrCL ≥30 mL/min) were not found to impact brigatinib exposure, suggesting no dose adjustment based on these covariates. In the exposure-response analyses, brigatinib exposure was not a significant predictor of response (≥partial response) or PFS. This suggests that the efficacy benefit was consistent across the range of exposures achieved with the 180 mg dosing regimen including after dose modifications. There was a significant relationship ( P< 0.05) between exposure and certain laboratory abnormalities (increased amylase and lipase). There was no relationship between exposure and CPK elevation, and brigatinib exposure had no effect on time to first dose reduction. Conclusions: These results support a favorable benefit/risk profile of the proposed 180 mg qd brigatinib dose (with a 7-day lead-in at 90 mg) for the front-line treatment of patients with ALK+ NSCLC. Clinical trial information: NCT02737501.
Single institution experience looking at efficacy of PD-1 inhibitors after progression on PD-L1 inhibitors or vice-versa in metastatic non-small cell lung cancer (NSCLC).
Authors: McGovern Kerri , Seetharamu Nagashree , Sullivan Kevin M.
Published: May 2020

e21726

Background: The treatment landscape for metastatic NSCLC has changed dramatically with emergence of checkpoint inhibitors (CPI). Even though all currently approved CPI target engagement of PD-1 with PD-L1 and have similar efficacy in NSCLC, there are some differences in their mechanisms of action. Current guidelines do not recommend switching to another CPI after progression of disease (POD) or toxicity on one CPI. For some patients, however, therapeutic options may be limited due to comorbidities, lack of trial prospects, performance status, or reluctance towards chemotherapy making switch to alternate CPI an attractive strategy. We report outcomes of patients who were treated with second CPI after POD on initial CPI for metastatic NSCLC between 2015 and 2019 at our institution. Methods: Data collection included demographics, clinic-pathologic factors, CPI agents, disease control rate (DCR), progression free survival (PFS), and immune-related adverse events (irAE). DCR was defined as response or stable disease based on RECIST. PFS was measured from date of initiation of CPI to POD or death. Results: Of 169 patients with NSCLC treated with CPI (median age 71 years, range 30-93), 26 received 2 lines of CPI. Two patients received first CPI as part of front line chemoimmunotherapy whereas all others received CPI alone. First CPI was PD-1 inhibitor in 20 patients and PD-L1 inhibitor in 6. DCR for first CPI was 88% and median PFS of 5 months (range: 1 –24). There were no irAE over grade 2 with initial CPI. Six patients were treated with PD-1 inhibitors after PD-L1, 16 with PD-L1 after PD-1, and 4 with an alternate agent in same class. Median PFS for 2nd CPI was 3 months (range: 1 - 36) for all patients and DCR for evaluable patients was 63% (n = 16). One patient experienced steroid-responsive grade 2 pneumonitis. Responses with either line of CPI did not correlate with PD-L1 expression. Conclusions: Our data suggests that switching from one CPI to another may be a reasonable, potentially effective option in select patient population. Prospective studies exploring this strategy is warranted.
EGFR gene mutation is not a significant prognostic factor in patients with EGFR mutated non-small cell lung cancer who receive best supportive care alone.
Authors: Masuda Takeshi , Wakabayashi Yu , Shimoji Kiyofumi , Yamaguchi Kakuhiro , Sakamoto Shinjiro , Nishimura Yoshihumi , Horimasu Yasushi , Nakashima Taku , Miyamoto Shintaro , Senoo Tadashi , Iwamoto Hiroshi , Iwamoto Hiroshi , Ohshimo Shinichiro , Fujitaka Kazunori , Hamada Hironobu , Hattori Noboru
Published: May 2020

e21736

Background: Epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), are less toxic than conventional chemotherapy drugs, and benefit patients with EGFR-mutated non-small cell lung (NSCLC) cancer. However, there are a few patients who are not able to receive EGFR-TKI due to poor performance status, older age, or sever comorbidities. Here, we aimed to determine the prognostic significance of EGFR mutation in NSCLC patients who received best supportive care (BSC) alone, and compare the anti-tumor outcomes of only EGFR-TKI-treated patients vs. BSC patients. Methods: We retrospectively reviewed the medical records of patients diagnosed with NSCLC at Higashihiroshima Medical Center during April 1991–January 2019 and Hiroshima University Hospital during April 2008–August 2018. Results: A total of 1163 patients diagnosed with unresectable NSCLC were included in this analysis. Of these 1163 patients, 234 patients received BSC alone.Among 196 patients who underwent EGFR mutation analysis, 38 and 158 did and did not harbor an EGFR mutation, respectively, and the mean survival times (MST) did not differ significantly between these groups (121 vs. 85 days, p = 0.789). Consistent with the survival analysis, the multivariate Cox regression analyses showed EGFR mutation was not an independent prognostic factor. After propensity score matching, a comparison of only EGFR-TKI-treated (n = 35) and BSC patients (n = 35) with EGFR mutation revealed that the former had a significantly longer MST than the latter (372 vs. 121, p < 0.001). Conclusions: EGFR mutation itself was not a significant prognostic factor in untreated NSCLC patients. The patients who received EGFR-TKI had a significantly longer MST than their untreated counterparts. Our results may help to explain the benefit of EGFR-TKI, particularly for patients who would be directed towards treatment with BSC.
Costs of extended immune check point inhibitors treatment in advanced/metastatic lung cancer: Bundling of costs proposal.
Authors: Guirgis Helmy M.
Published: May 2020

e21738

Background: Pembrolizumab (Pembro) demonstrated remarkable 5-year overall survival (OS) and hazard ratios (HR) in 1st-line advanced/metastatic lung cancer (amLC) lacking EGFR and ALK alterations. After 35 cycles or 2 years, there is no consensus on whether to continue or stop the immune check point inhibitors (ICI). In contrast to ICI receiving no cost adjustment, CAR T-cell were contained at $375,000-$400,000. Probability of survival (PoS) was previously expressed as (1.0- HR) and used as surrogates of outcome. Our objective was to weigh ICI costs at one year and beyond vs PoS. Methods: Costs of Durvalumab (Durv) 10mg/Kg iv were calculated in US dollars q2 weeks. Pemetrexed (Peme) 500 mg/m2, Atezolizumab (Atezo) 1200 mg and Pembro 200 mg were computed q3 weeks. HR at the 95% confidence levels were quoted and PoS calculated. Results: The average ICI yearly-costs were $153,053, increasing annually by 2-4%. Peme were $108.108 and PoS 0.22. One-year adjuvant Durv in unresectable stage III were $145,808 at PoS 0.47. Pembro were $157,213 and PoS 0.40 in PD-L1 > 50%. Pembro costs beyond 5-years exceeded $786,065. Pembro- Peme-carboplatin in non-squamous histology were $265,321. PoS was 0.41 in PD-L1 < 1% and 0.58 in > 50%. Atezo+Bev 4-drug-costs were higher at $389,134 with modest 0.22 PoS. Setting mono-theray ICI yearly-costs at $160,000, one patient treated for 3 years would pay $480,000. Bundling costs at $400,000-$450,00 would save $30,000-$80,000. Savings would multiply with further years of extension. Conclusions: At 0.47 PoS, the one-year cost of adjuvant Durv was worth the dollars spent. The runaway ICI costs beyond 2 years would support the cost bundling proposal.
TP53 fusions with next-generation sequencing (NGS) in Chinese non-small cell lung cancer (NSCLC): A multicenter study.
Authors: Chen Huafei , Wang Wen xian , Xu Chunwei , Zhu You-cai , Zhuang Wu , Huang Yun-jian , Fang Yong , Wang Hong , Zhang Yinbin , Wang Yafei , Chen Meifang , Li Jinluan , Wang Liping , Cai Shangli , Fang Meiyu , Chen Gang , Lv Tangfeng , Song Yong
Published: May 2020

e21742

Background: Currently, with the advances in detection techniques, such as next generation sequencing (NGS), more and more rare or atypical TP53 fusions had been identified. Such as TP53-PSMD14, the importance of EGFR signaling in the pathogenesis of lung cancer and the efficacy of EGFR-TKI treatment had been demonstrated. The aim of this study was to evaluate the prevalence of TP53 fusions in Chinese NSCLC populations, which had not been reported earlier, and to describe targeting potential in Chinese NSCLC populations. Methods: A multicenter study in China was initiated from February 2014, and NSCLC patients have been enrolled as of December 2018. A total of 2743 patients with NSCLC were screened by using next-generation sequencing (NGS)-based 381 genes panel assay for detecting TP53 fusions. Results: Of this entire cohort, just four (0.15%) patients were identified with a TP53 fusion, including DNAH2-TP53 (1), TP53-MPDU1 (1), TP53-FXR2 (1), TP53-VEZF1 (1). Of the TP53 fusion NSCLC patients, 50.00% were detected in female patients. Biopsies were obtained from primary lung tumor (25.00%) and metastatic sites (75.00%). Overall TMB in the TP53 fusion was high, which had more than 20 mut/Mb. Of the TP53 fusion NSCLC, two cases (50.00%) featured EGFR SV alterations. Conclusions: The frequency of TP53 fusions in Chinese populations with NSCLC is extremely rare (0.17%). TP53 fusions may reduce responsiveness to TKIs and worsen prognosis in EGFR-mutated NSCLC patients, mainly those carrying exon 19 deletions or exon 21 L858R.
Clinical characteristics and treatment outcomes of 65 patients with BRAF-mutated non-small cell lung cancer (NSCLC).
Authors: Mu Yuxin , Yang Ke , Hao Xuezhi , Wang Yan , Wang Lin , Liu Yutao , Lin Lin , Junling Li , Xing Puyuan
Published: May 2020

e21745

Background: BRAF mutations are infrequently seen in non-small cell lung cancer (NSCLC) in Chinese population. We aimed to investigate the clinicopathologic characteristics and treatment outcomes of Chinese patients with NSCLC harboring BRAF mutations. Methods: We conducted a retrospective multicenter study in China of patients with NSCLC harboring BRAF mutations between Jan 2017 and Jul 2019. Results: A total of 65 patients treated in 22 centers were included, 54 harbored BRAF-V600E mutation and 11 had non-V600E mutations, including K601E, G469S, G469V, G469A, G596R, G466R and T599dup. No significant difference in age or gender was found between BRAF-V600E and non-V600E cases, while the majority of patients with non-V600E mutations were smokers (81.8%). Of the 18 patients with early-stage disease at diagnosis and underwent a resection, the median disease-free survival (DFS) was 43.2 months, 18.7 months and 10.1 months of stage I, II and IIIA patients (P = 0.07), respectively. In 46 patients with advanced-stage disease at data cutoff, disease control rate (DCR) and progression-free survival (PFS) of first-line anti-BRAF targeted therapy was superior than chemotherapy in patients harboring BRAF-V600E mutation (DCR, 100.0% vs. 70.0%, P = 0.027; median PFS, 9.8 months vs. 5.4 months, P = 0.149). Of 30 V600E-mutated patients who received anti-BRAF therapy during the course of disease, the median PFS of vemurafenib, dabrafenib, and dabrafenib plus trametinib was 7.8 months, 5.8 months and 6.0 months, respectively (P = 0.970). Median PFS were similar between V600E and non-V600E patients (5.4 months vs. 5.4 months, P = 0.825) to first-line chemotherapy. Nine patients were treated with checkpoint inhibitors, DCR and median PFS were 62.5% and 3.0 months (95%CI 2.9, 3.1), respectively. Conclusions: Our data demonstrated the clinical benefit of anti-BRAF targeted therapy in Chinese NSCLC patients harboring BRAF-V600E mutation. The value of immunotherapy and treatment selection among non-V600E population needs further study.[Table: see text]
The efficacy of anti-PD-1 combined with temozolomide in unresectable, advanced melanoma from one center.
Authors: Hu Tu , Sun Wei , Xu Yu , Luo Zhi-Guo , Chen Yong
Published: May 2020

e22007

Background: Anti-PD1/PDL-1 immunotherapy has led to a new era of the unresectable, advanced melanoma treatment. However, there are still a significant part of patients suffer from primary or secondary drug resistance to immunotherapy. We sought to explore the efficacy and safety of anti-PD-1 plus Temozolomide in unresectable, advanced melanoma patients. Methods: Patients with unresectable, advanced melanoma were treated with anti-PD-1 plus Temozolomide, Temozolomide/DTIC based chemotherapy, or anti-PD-1 alone between 1 May, 2018 and 31 January, 2020. Data were retrospectively reviewed and statistically analyzed for best ORR and progression free survival, as well as toxicities. Results: Seventy-seven individuals were identified, including 37 (48.1%) with acral melanoma, 20 (26.0%) with cutaneous melanoma, 16 (20.8%) with mucosal melanoma and 4 (5.2%) with melanoma of unknown primary. Thirty-three (46.8%) patients had received postoperative adjuvant treatment before progression, and none of them had received anti-PD-1 treatment. The objective response rate of anti-PD-1 plus Temozolomide (n = 5, 41.7%) was higher than Temozolomide/DTIC (n = 1, 5%) or anti-PD-1 alone (n = 6, 20.7%) in the front-line therapy and second-line therapy (42.9%, 0%, 23.5%, respectively). Similar results were found in the third-line therapy. Although no significant difference was detected among these groups in the front-line therapy, the progression free survival of anti-PD-1 plus Temozolomide (median, 7 months) was higher than Temozolomide/DTIC (median, 2.5 months) (p = 0.009), while showing no significant difference with anti-PD-1 (median, 4.5 months) (p = 0.267) in the second-line therapy. The incidence of grade 3/4 toxicity was 8% (anti-PD-1 plus Temozolomide), 20.7% ( Temozolomide/DTIC) and 23.8% (anti-PD-1) respectively, mainly immunogenic pneumonia (0%, 0%, 10.3%) and hepatotoxicity (0%, 4.8%, 6.9%), and no significant difference was found among these groups. Conclusions: The efficacy of combination of anti-PD-1 and Temozolomide is better than Temozolomide/DTIC or anti-PD-1 alone in advanced melanoma and does not increase the toxicity. Therefore, Anti-PD-1 combined with Temozolomide may be used as front-line regimen in advanced melanoma.
Clinical experience with the targeted therapy in melanoma patients with brain metastases.
Authors: Zhukova Natalia V. , Orlova Rashida , Antimonik Nina , Beliak Natalia P. , Kutukova Svetlana , Vasyusina Olga , Popova Natalia V.
Published: May 2020

e22009

Background: According to the clinical studies, the frequency of melanoma brains metastasis reaches 43%, and according to autopsy data, this percentage is even higher - up to 75%. New drugs in clinical practice has significantly improved the prognosis of the metastatic melanoma, however, patients with metastases in the brain are often excluded from large clinical studies, which limits the evidence base of the effectiveness of new therapy methods in this category of patients. Methods: 44 patients with advanced melanoma were treated in SPb Clinical Oncology Dispensary from 2012 till now: 19 male and 25 female, median age is 54y.o. (from 26 to 81). 31 (70%) patients received combination of BRAF and MEK inhibitors, 13 (30%) patients received only BRAF inhibitors. 26 (59%) of patients received target therapy (TT) as 1st line of therapy. Initial performance status (PS) assessed by ECOG scale was following; 8 patient had PS = 0 by ECOG, 29 patients – PS = 1 by ECOG and 6 patients had PS = 2/3 status by ECOG. 8 (18%) patients with brain metastasis has radiation before the TT: 6 patients received at least 1 session of stereotactic radiotherapy and 2 patients underwent radiation of the entire brain. Results: Group of patients without brain metastases: median PFS is 10.0 month (95% CI: 6.0;15.0). The average PFS is 16,90 ± 3,19 month (95% CI:10,64;23,16). Median OS is 15.0 months (95% CI: 11.0;64.0). The average OS is 33,16 ± 5,89 month (95% CI: 21,62 – 44,70). Group of patients with brain metastases: median PFS and OS is not reached. The average PFS is 17,86 +/- 3,3 month (95% CI: 11,42-24,33). The average OS is 20,31 ±2,86 month (95% CI: 14,71 - 25,92). Only 3 from 8 patients have PD after TT on the time of analysis. 5 patients are still alive. Conclusions: Our clinical experience demonstrates comparable efficacy of TT (PFS and OS) in patients with melanoma, regardless of the presence of metastatic brain disease. In the treatment of this category of patients, an integrated approach is very important, including both the use of targeted drugs and the conduct of surgical and radiotherapy. An equally important factor is the rapid onset of treatment.
Safety and efficacy of checkpoint inhibitors in solid organ transplant recipients with cutaneous squamous cell carcinoma.
Authors: Tsung Irene , Worden Francis P. , Fontana Robert J.
Published: May 2020

e22014

Background: Immune checkpoint inhibitors (ICI) are increasingly used in solid organ malignancies. However, data are limited regarding their safety and efficacy in solid organ transplant (SOT) recipients at risk for allograft rejection. The aim of this study was to review our experience with ICIs in SOT recipients at a large transplant center. Methods: A retrospective review of ICIs used in SOT recipients from April 2011 to September 2019 was undertaken. Patient clinical and demographic features, ICI regimen, immunosuppression, allograft function, and efficacy were reviewed. Results: There were 8 SOT recipients (3 kidney, 4 liver, 1 lung) with 7 diagnosed with metastatic head and neck (H&N) cutaneous squamous cell carcinoma (cSCC) and 1 with Merkel cell carcinoma. At a median of 150 months [79-219] post-transplant, 6 were treated with cemiplimab and 2 with pembrolizumab after minimizing calcineurin inhibitors (CNI). Overall tumor response was 37.5% at a median of 3.8 months [0-8] of follow-up. However, 3 died of tumor progression and 2 of other causes at a median of 55 days [8-214] after starting ICI. The only irAE reported was severe pneumonitis in one patient requiring intubation and ICI discontinuation but responded to steroids. Two patients received prophylactic steroids and have preserved allograft function and ongoing tumor response at month 6. Conclusions: Our data suggest that minimization of CNI along with judicious use of prophylactic steroids may allow for the safe use of ICIs in SOT recipients with advanced H&N cSCC. Short-term efficacy appears promising and prospective studies are warranted. [Table: see text]
Influence of age and cancer history on prevalence of autoimmunity in patients with metastatic melanoma: A large retrospective study.
Authors: Holmes Aaron N. , Wang Xiaoyang , Swede Helen , Hegde Upendra P.
Published: May 2020

e22016

Background: While immune checkpoint inhibitors (ICIs) have improved the survival rates of metastatic melanoma in recent years, immune-related adverse events (irAEs) remain a major toxicity. Studies have established that pre-existing autoimmunity increases the risk of severe irAEs following ICI therapy (1). Melanoma is common cancer in older patients, and older age is believed to be a risk factor of autoimmunity. However, there is controversy concerning the influence of age increasing the risk of irAEs between clinical trials, which exclude patients with confirmed or suspected autoimmunity, and less-selective but lower-power case reports (2). In order to understand potential irAE risk following ICI treatment, we measured the prevalence of pre-existing autoimmune disease by age and cancer type. Methods: We studied 293,938 patients aged 18-106 years old who were treated at the University of Connecticut Health Center between 2000 and 2018 using GE Centricity’s IDX database. Patients were organized into four study groups based on International Classifications of Diseases codes (ICD-9 and ICD-10), specifically primary melanoma and three comparisons groups: non-cutaneous neoplasms alone, melanoma with non-cutaneous neoplasms, and patients without cancer history. A list of 340 ICD codes corresponding to 105 autoimmune conditions were queried. Results: Non-cutaneous cancer, in the absence or presence of melanoma, was associated with a higher prevalence of autoimmunity (27.0%, 29.4%, respectively) compared to the rates in patients with melanoma alone and those without cancer history (11.1%, 8.7%, respectively, p < 0.05). In patients with both melanoma and non-cutaneous cancers, those with metastases had an 11.7% increase in autoimmune prevalence compared to patients without metastases (p < 0.0001), the largest metastasis-associated increase observed across all cancer groups. Lastly, a logistic regression demonstrated that age is weakly correlated with autoimmunity (r = 0.01, p < 0.0001). Conclusions: The findings suggest that a history of metastasis, non-cutaneous cancer, and advanced age are associated with a higher prevalence of pre-existing autoimmunity in melanoma patients. As ICIs are indicated for metastatic melanoma, our findings warrant future studies and careful risk assessment of autoimmunity in senior patients.
Vitiligo is correlated with clinical benefits in patients with advanced cutaneous melanoma treated with immune checkpoint inhibitors (ICI).
Authors: Martin Reinas Gaston , Muino Marcelo , Abal Mariana , Garcia Gerardi Carlos , Tognelli Flavio , Gil Deza Ernesto , Gonzalez Cesar , Gonzalez Liliana D , Nunell Marcelo Andres , Marin Ordoñez Alba , Morgenfeld Eduardo L. , Rivarola Edgardo G. J. , Gercovich Felipe G.
Published: May 2020

e22023

Background: Use of ICI changed the treatment of Advanced Cutaneous Melanoma Patients (ACMP). This paper analyzes the evolution of ACMP who develop vitiligo during ICI treatment at Instituto Oncológico Henry Moore (IOHM). Methods: We selected all ACMP that received ICI between August 2015 and December 2019. We collected clinical data and compared Group A (ACMP with vitiligo) with Group B (ACMP without vitiligo) on: response rate (RR), time from ICI treatment initiation to progression (TTP) and overall survival (OS), defined as time from ICI treatment initiation to death. Outcomes were assessed using table tests and Kaplan-Meier curves with log-rank test. Results: Out of 32 ACMP treated with ICI, 12 Pt (37%) were in Group A and 20 Pt (63%) were in Group B. Table shows group characteristics and outcomes. Conclusions: 1) During treatment with ICI, 12 out of 32 (37%) advanced cutaneous melanoma patients were afflicted with vitiligo. 2) Two out of three patients who responded to ICI treatment developed vitiligo and obtained better TTP and OS than those without vitiligo. 3) According to these results, vitiligo is the consequence of the immune system reactivation responsible for considerable clinical benefits. Further studies should analyze if it is feasible to reduce ICI doses in patients who develop this adverse effect. 4) In this small and retrospective series, Nivolumab was more frequently correlated with vitiligo and clinical benefits, but we need prospective studies to decide which ICI treatment is the most effective. [Table: see text]
Retrospective analysis of retreatment with Ipilimumab in patients with metastatic melanoma.
Authors: Formozo André Alexandre , Gomes Jessica Ribeiro
Published: May 2020

e22032

Background: The checkpoint inhibitors are effective in the treatment of many types of neoplasia, either being used separately or in combination. Ipilimumab pioneered the treatment of metastatic melanoma and nowadays it has being used in combination with anti-PD1. Retreatment with Ipilimumab has rarely been reported, but it may be an important strategy for the current treatment of metastatic melanoma. In this study we analyzed the patients with metastatic melanoma who were retreated with Ipilimumab. Methods: We evaluated patients with metastatic melanoma who had benefited from the first treatment with Ipilimumab, but eventually had progression of disease. They received Ipilimumab at the same dose as the first treatment (3 mg/kg every 3 weeks for four cycles). The effect was evaluated for progression free survival and clinical benefit. Results: Twenty–two patients were retreated with Ipilimumab in our Oncology Center. Most of them retreated six months or more, after the prior treatment. The progression free survival of the first treatment with Ipilimumab was 9.9 months. The median progression free survival of the retreatment was 6.3 months. Fourteen patients were reported to have clinical benefit (63%). Conclusions: This is a retrospective evaluation about the retreatment with Ipilimumab in patients with metastatic melanoma. It has been rarely reported in the medical literature, especially Ipilimumab at doses of 3 mg/kg. Maybe the next step might be the combined retreatment with Ipilimumab and anti-PD1.
Real-world treatment patterns and clinical outcomes of advanced melanoma patients following disease progression on anti-PD-1-based therapy.
Authors: Hernandez-Aya Leonel Fernando , Burke Matthew , Collins Jenna M , Earle Dennis , Hamilton Melissa , Nordstrom Beth L , Zhang Ying , Srivastava Shivani
Published: May 2020

e22036

Background: Despite the success of anti-programmed cell death-1 (PD-1) based therapies that prolong survival in advanced melanoma, some patients experience disease progression. Real-world treatment patterns and outcomes after progression on anti-PD-1 based regimens are unknown. Methods: Adults with advanced melanoma and a record of disease progression on anti-PD-1 treatment (alone or in combination) between 1 Sept 2014–31 Jan 2019 were selected from the Flatiron Health Oncology electronic medical record (EMR) database for this retrospective study. Index progression date was defined as an event where the treating clinician concluded in the patient record that there had been disease progression. The first subsequent therapy received was identified. Kaplan-Meier methods estimated overall survival (OS) with 95% confidence interval (CI) after the progression date. Analyses were run separately for BRAF mutant (mt) and wild type (wt). Results: Among 2,169 patients with advanced melanoma treated with an anti-PD-1, 213 BRAFmt and 302 BRAFwt had a record of progression following anti-PD-1 initiation and were included; an additional 82 BRAFmt and 138 BRAFwt were excluded due to death without a record of progression. Median age was 64 and 71 years, respectively; 27.7% and 9.9% had >1 line of therapy prior to the anti-PD-1. Among the BRAFmt patients who progressed on anti-PD-1, 94 (44.1%) received no subsequent therapy, 80 (37.6%) BRAF±MEK (± IO), and 16 (7.5%) anti-CTLA4 alone or with anti-PD-1 after progression on the initial anti-PD-1; 11% received other treatments with no clear pattern of care. Median (95% CI) OS from the index progression date for BRAFmt was 11.9 (8.2–16.9) months. In a subgroup of these BRAFmt patients with BRAF treatment prior to or during the first anti-PD-1 line (N = 65), 52.3% had no subsequent therapy and a median OS of 4.0 (2.7–7.5) months. Among the BRAFwt patients who progressed on anti-PD-1, 186 (61.6%) received no subsequent therapy, 46 (15.2%) received anti-CTLA4 alone or with anti-PD-1, 26 (8.6%) switched anti-PD-1s, and 15% received other treatments. Median (95% CI) OS for BRAFwt was 10.1 (8.8–12.5) months. Conclusions: In this real-world retrospective study, > 40% of BRAFmt and > 60% of BRAFwt patients did not initiate a new regimen after progression on anti-PD-1 therapy. Median OS after progression was < 1 year. This may be overestimated, as it excluded patients who died before progression was recorded in the EMR. These findings highlight a need for more effective treatments for advanced melanoma.
The use of PET/CT to detect early recurrence after resection of high-risk stage III melanoma, prior to the start of adjuvant therapy and during follow-up.
Authors: Van Der Hiel Bernies , Stahlie Emma H.A. , Stokkel Marcel P , Wouters Michel W.J.M. , Schrage Yvonne , van Houdt Winan J. , Van Akkooi Alexander Christopher Jonathan
Published: May 2020

e22039

Background: To date, international consensus concerning the use of PET/CT as a surveillance tool in the follow-up of high-risk melanoma patients after complete resection of disease is lacking. Moreover, with the rise of adjuvant therapy it seems appropriate to investigate the role of this imaging modality to exclude newly developed metastases after resection and prior to starting treatment. The aim of this study was to investigate the use of PET/CT as surveillance tool in the follow-up and prior to adjuvant therapy in asymptomatic patients with complete resection of stage IIIB and IIIC melanoma. Methods: Prospectively two cohorts were set up with stage III melanoma patients with complete resection of disease. In the first cohort (stage IIIB/C AJCC 7th) surveillance PET/CT was performed 6-monthly for two years if patients stayed asymptomatic with normal serum S100B, with a final scan at three years. In the second cohort (stage IIIB/C/D AJCC 8th) patients underwent one screening PET/CT after resection and prior to starting adjuvant treatment. Results: Eighty patients entered follow-up in cohort 1. Of these, the majority did not undergo surveillance scans, because they required treatment for newly detected clinical metastases. Thirty-five patients remained asymptomatic and were included in surveillance cohort one (105 scans) with a median follow-up of 33 months. Twelve patients (34%) developed a recurrence, seven (20%) of which were detected on the first scan at six months. Seven recurrences involved stage IIIC patients, five stage IIIB patients. Sensitivity and specificity were 92% and 100% respectively. Forty-two patients were included in cohort 2. Recurrence was suspected on nine scans, four (10%) of which were true positive. One patient proceeded to undergo a node dissection and then started adjuvant therapy. The other three patients had progressed to stage IV and therefore started radiotherapy and/or systemic immunotherapy. Five (12%) scans were false positive, the suspected lesions were not related to the preceded surgery. The number of scans needed to find one asymptomatic recurrence were 8.8 and 10.5 in cohort one and two, respectively. Conclusions: This study shows that PET/CT is a useful surveillance tool for detecting recurrence in asymptomatic high-risk resected stage III melanoma patients, especially within the first six months after surgery and therefore should be considered when monitoring these patients during follow-up as well as prior to starting adjuvant therapy.
Efficacy of immune checkpoint inhibitors for the treatment of metastatic melanoma (MM) in patients with concurrent chronic lymphocytic leukemia (CLL).
Authors: Guerra Veronica , Ologun Gabriel O. , Haydu Lauren Elaine , Keung Emily Zhi-Yun , Burton Elizabeth M. , Tawbi Hussein Abdul-Hassan , Wierda William G. , Davies Michael A. , Wargo Jennifer Ann , Ferrajoli Alessandra
Published: May 2020

e22044

Background: Patients with CLL have immune impairment with abnormalities in T-cell subset composition and immune synapse formation. The impact of these defects on response to immune checkpoint inhibitors (CPI) is not known. Given the high incidence of melanoma in patients with CLL we sought to evaluate the response to CPI in patients with concomitant MM and CLL. Methods: Retrospective analysis of 24 patients (pts) with concurrent CLL and MM who received a total of 38 CPI therapies between July 1997 and July 2019. Primary objective was to determine objective response rate (ORR), defined as complete response (CR) or partial response (PR) by RECIST1.1. Secondary outcomes included event-free survival; overall survival (OS), and duration of response (DOR). Results: The median age at CLL and melanoma diagnosis was 62 and 63 years, respectively. 71% of patients were male. Most presented with early stage CLL at diagnosis (67%), 60% had mutated IGVH, and 47% had deletion of 13q by FISH. 71% remained on observation for their CLL. Median time from melanoma diagnosis to CPI initiation was 13.5 months. 83% had stage IV MM and 17% stage III MM at the time of therapy. 17% had increased LDH. The most common melanoma mutations were BRAF(35%), BRAFV600 (26%), TP53 (30%) and NRAS (26%). Median follow up was 37 months and the ORR was 24% (Table). Median DOR was 41 months and median OS is 26.4 months. Immune-mediated adverse events occurred in 42%, including 13% fever, 11% thrombotic events, 8% endocrine dysfunction. 13 pts are alive and 11 pts died (8 pts due to MM progression). There were no significant changes in absolute lymphocyte counts during CPI therapy. 2 pts received CPI while on ibrutinib or ibrutinib+venetoclax therapy with ongoing CLL responses. Conclusions: Our experience indicates that CPIs can be effective for the treatment of MM in patients with concurrent CLL, achieving durable responses. Immuno-mediated toxicities were frequently observed. A lower ORR was observed in first-line CPI in MM, however the numbers of pts are small. Further studies are needed to determine if initial or concurrent treatment for CLL could improve CPI outcomes and survival. Additional studies evaluating T cells function and tissue infiltration in these patients are ongoing. [Table: see text]
Pathway-flux based biomarker for immunotherapy response in melanoma.
Authors: Li Jian , Mei Qi , Cheng Weiting , Hu Guangyuan , Yuan Xianglin , Mansmann Ulrich Robert
Published: May 2020

e22064

Background: Immune checkpoint therapy (ICT) refers to therapeutic interventions that specifically target immune evasion mechanisms to restore the host immunity with anti-tumor ability. The ICT has revolutionized the immune-based treatment across > 30 different cancers including solid tumors and hematopoietic malignancies, with an ORR of 30% and a 7%-12% grades 3-5 irAEs in average. However, a substantial unmet point is the development of a biomarker with which response of ICT can be predicted before treatment for individual patients. Methods: In order to face this challenge this study developed an advanced genome-scale pathway flux analysis (GPFA) to evaluate the strength of signaling transduction and metabolic flux in immune system. The input of GPFA is the gene expression profiles of individual objects and the output of GPFA can be summarized in a index system, IM.Index, with following definition: IM.Index = 1.78E-4 * Σ flux(P) + 2.37E-4 * Σ flux(P) p ∈ signaling transduction p ∈ energy metabolism. Subsequently, the IM.Index was applied to analyze genetic data of two independent cohorts of melanoma patients treated with anti-PD-1 therapy (nivolumab a. pembrolizumab). Results: The IM.Index predicted the response of anti-PD-1 therapy (nivolumab) in the first cohort with an odds ratio (OR) of 3.14 (95%CI: 1.16-8.45; p = 3.10E-3; AUC = 0.82) and with a sensitivity 89% and specificity 76%. The prediction on overall survival (OS) of this cohort achieved an hazard ratio (HR) of 1.53 (95%CI: 1.22-1.92; p = 7.8E-3). Subsequently, the prediction result for the anti-PD-1 therapy (pembrolizumab) in the second cohort achieved an OR of 2.12 (95%CI: 1.22-3.66; p = 4.50E-4; AUC = 0.87) and the OS prediction in this cohort reached an HR of 1.24 (95%CI: 1.04-1.47; p = 1.40E-2). Comparison with other four potential biomarkers (TMB, TNB, neo-peptide load and cytolytic score) related to immunotherapy showed a comparative outcome of the IM.Index regarding diagnosis and prognosis in melanoma. For instance, IM.Index showed a superior performance on objective response rate (ORR) of 70% and AUC of 0.83. Conclusions: In conclusion this study demonstrated that a pathway flux analysis at a genome-scale may be explorative in biomarker research in immunotherapy, since this type of analysis could reflect the strength or functional status of the immune system. The IM.Index developed in this study may also be applied to investigation the treatment response of immunotherapy in other types of cancer.
Treatment of locally advanced or multiple basal cell carcinoma with vismodegib in real world setting.
Authors: Ocvirk Janja , Mesti Tanja , Leskovsek Katja
Published: May 2020

e22065

Background: Evaluation of efficacy and safety of vismodegib (V) was done in a retrospective analysis of patients (pts) with locally advanced or multiple basal cell carcinoma (laBCC or multiple BCC) and pts with Goltz-Gorlin Syndrom (G-G Syn) in routine clinical practice. Methods: Baseline characteristics, efficacy data and treatment-related adverse events were collected from 30 laBCC or multiple BCC and 6 G-G Syn pts who were treated with V. Results: In 86-month period, 36 pts were diagnosed with laBCC (18 pts), multiple BCC (12 pts) or G-G Syn (6 pts), all inappropriate for surgery or radiotherapy. Baseline characteristics: median age was 72.6 years in laBCC + multiple BCC pts group and 51.3 years in G-G Syn pts group. Sixty percent of pts in laBCC + multiple BCC group were females; majority (70%) of pts were previously treated by surgery (S) and/or radiotherapy (RT); 43% of pts had 1 lesion with predominant localization in central face (eyes, nose, lips or ears in 84% of pts), 20% had 2-3 lesions and 37% more than 3 lesions. Fifty percent of pts in G-G Syn pts group were males; all pts were previously treated with S and/or RT. The overall response rate (ORR) was 76% in laBCC + multiple BCC and 83% in G-G Syn pts group. Disease control rate (DCR) was 93% in laBCC + multiple BCC and 100% in G-G Syn pts group. Median duration of treatment (DoT) was 7.8 months (range: 1.3-29.8) in laBCC + multiple BCC group and 27.1 months (range: 4.8-86.4) in G-G Syn group. At the time of analysis in laBCC or multiple BCC group one patient died due to other reasons than cancer, in 30% of pts treatment has been interrupted during the treatment course [in most cases due to complete response or adverse events (AEs)], 40% of pts are still on treatment. In G-G Syn group treatment has been interrupted in 50% of pts (in most cases due to adverse events), 67% of pts are still on treatment. AEs of any grade were reported in 97% of pts in laBCC or multiple BCC group and 83% in G-G Syn group. Majority of AEs in laBCC or multiple BCC group were grade 1 or 2 (96%)., 4% of AEs were grade 3: muscle cramps in 3 pts, respiratory infection, vomiting and anemia in 1 patient each. Majority of AEs in G-G Syn group were also grade 1 or 2 (87%), 13% of AEs were grade 3: muscle cramps in 2 pts, weight loss and diarrhea in 1 patient each. No grade 4 or 5 AEs were reported. Conclusions: Vismodegib has shown meaningful efficacy with manageable safety profile in pts with laBCC or multiple BCC as well as in pts with G-G Syn in real world setting.
Genomic landscape of malignant peripheral nerve sheath tumor (MPNST)-like melanoma.
Authors: Pimentel Muniz Thiago , Sorotsky Hadas , Kanjanapan Yada , Rose April A. N. , Araujo Daniel Vilarim , Fortuna Alexander , Ghazarian Danny K. , Saeed Kamil Zaid , Pugh Trevor John , Mah Michelle , Thiagarajah Madhuran , Spreafico Anna , Hogg David
Published: May 2020

e22072

Background: Malignant Peripheral Nerve Sheath Tumor (MPNST)-like melanoma is a rare entity wherein cutaneous melanoma mimics histomorphological features of MPNST. The genomic landscape of MPNST-like melanoma has not been previously described. We report the genomic findings of 6 patients diagnosed with MPNST-like melanoma. Methods: We identified consecutive patients with confirmed histological diagnosis of MPNST-like melanoma. Archival tissue was submitted for whole exome and transcriptome sequencing analysis and genomic findings were compared to publicly available data on the genomic landscape of both melanoma and limited genetic descriptions of MPNST. Results: Six patients diagnosed with MPNST-like melanoma between November 2002 and July 2018 had archival tissue available (8 samples). Mean age at diagnosis was 60.5 years (38-74). The mean tumor mutational burden (TMB) was 35.72 mutations/exon coding megabase, ranging from 4.27 to 86.36. NF1 alterations were found in 4 (67%) of cases: one had 3 truncating mutations (W696 + X1870_splice + R1590C) associated with NF1 amplification, one had a deep deletion and another two had truncating mutations (I1908L and W696 + A1530V). Two tumors had non-V600 BRAF mutations that predict alteration in kinase function. We observed deletions of cell cycle regulators: CDKN2A and CDKN2B in 33%; and ZNF331 (19q13.42) in 83% of cases. SERPINB4 (18q21.3), described previously as a tumor suppressor in oral squamous cell carcinomas, was deleted in all samples. The patient with NF1 amplification and truncating mutations received immunotherapy due to metastatic disease and achieved a complete response; his tumor had a TMB of 72.6. Another patient who died of metastatic melanoma, treated with chemotherapy in the pre-immunotherapy era, lacked any NF1 mutation but had a Q61K NRAS mutation; the tumor had a TMB of 15. The remaining patients were treated with surgical resection alone and continue on follow-up. Conclusions: MPNST-like melanoma shares some frequently altered genes in cutaneous melanoma but possesses an excess of NF-1 mutations or deletions, in keeping with its neural-like phenotype. The high frequency of SERPINB4 alterations suggests a critical tumor suppressor role in this subtype of melanoma, warranting further investigation. Additionally, cell cycle dysregulation caused by deletion of ZNF331 and CDKN2A/B may be important in MPNST-like melanoma carcinogenesis.
Exosomal microRNA in serum is a prognostic factor in cutaneous squamous cell carcinoma.
Authors: Choi Jonggwon
Published: May 2020

e22073

Background: Functional microRNA(miRNAs) is located in the area of the gene related to cancer, such as inside of oncogenes and tumor suppressor genes, loss of heterozygocity or fragile site. There are many studies show that abnormal increase expression of miRNAs when cancer occurs. While some miRNAs commonly suppress abnormal expression of tumors, they can also infer the orgin of tumor tissues because they are more often representative of unique miRNA depending on type of tumor. In many case, the miRNAs expression patterns provide more characteristic information about tumors than messenger RNA expression profinling. The miRNAs expression patterns, which have changed with tumor types, provide clue that can serve as a biological markers for diagnosis, determining the outcome of disease, and predicting treatment responses. Indeed, several studies have reported thatextracellular miRNA is related to the prognosis of disease in some cancers, such as colon cancer and breast cancer. However, so far, there is no study that has been no defenitive study on how exosomal miRNAsare related to progrosis in cutaneous squamous cell carcinoma. We studied the association between the patient’s prognosis and miRNAs detected in cancer tissue and blood serum. Methods: We analyzed 35 patients who have various stage of cutaneous squamous cell carcinoma. Cancer tissue and serum samples were sequentially obtained. The miRNAs were prified from serum exosome and cancer tissues, and miRNAs sequencing was performed. The miRNAs expression profiles and copy number variations were observed using next generation sequencing (Hiseq, illumina inc) in 35 cancer tissues and serum samples. We validated miRNAs change and patient’s prognosis. Results: miR-142-5p cluster expression level in serum exosome and cancer tissue was most correlated with poor prognosis of cutaneous squamous cell carcinoma. Exosomal miR-142-5p expression level in serum were significantly higher(P < 0.01) in patients with late stage than in patients with early stage. Also, the patients with recurrence showed high level of miR-142-5p. Conclusions: miR-142-5p expression level may be an important marker for predicting the patient’s prognosis and deciding whether undergo additional systemic chemotherapy after surgery.