Availability Of Immunotherapy Research Articles

Real-world treatment patterns and survival outcomes for patients with stage III non-small cell lung cancer in Spain: a nationwide cohort study.

The burden of non-small cell lung cancer (NSCLC) remains high in Spain, with lung cancer accounting for 20% of cancer-related deaths annually. Programs such as the Spanish Thoracic Tumour Registry (TTR) and the global I-O Optimise initiative have been developed to observe patients in clinical practice with the aim of improving outcomes. This analysis examined treatment patterns and survival in patients with stage III NSCLC from the TTR. These patients represent a heterogenous group with complex treatment pathways. The TTR is an ongoing, observational, prospective, and retrospective cohort multicentre study (NCT02941458) that follows patients with thoracic cancer in Spain. Adults aged ≥18 years with stage IIIA/IIIB NSCLC enrolled in the TTR between 01 Jan 2010 and 31 Oct 2019 were included in this analysis. Initial treatment received was described by cancer stage and histology (squamous and non-squamous NSCLC). Kaplan-Meier estimates of progression-free survival (PFS) and overall survival (OS) were calculated over a 5-year period. A total of 1,838 patients were included in the cohort, including 1,082 with stage IIIA (58.9%) and 756 with stage IIIB (41.1%). Median follow-up was 18.3 months. The median age of patients was 66 years, and most had non-squamous NSCLC (54.0%), were male (81.2%), and were active or former smokers (93.4%). Overall, 26.3% of patients received surgical resection (37.0% for stage IIIA and 11.1% for stage IIIB). The most frequent initial treatment received was concurrent chemoradiotherapy for stage IIIA (30.2%) and stage IIIB (37.0%) patients. Median OS was lower in patients with stage IIIB than stage IIIA (28 vs. 37 months) disease and was lower for patients with squamous than non-squamous histology (19 vs. 26 months). Median PFS and OS varied when patients were stratified by initial treatment. This TTR analysis describes the clinical reality surrounding the initial management and survival outcomes for stage III NSCLC in Spain and presents survival outcomes comparable with other real-world evidence. It provides insights into the diverse approaches used before the availability of immunotherapies and targeted treatments in the non-metastatic NSCLC setting.

Survey of Skull Base Surgeons' Approach to Carcinomas Involving the Cavernous Sinus.

Objectives Carcinomas involving the cavernous sinus are challenging to resect without compromising important neurovascular structures. Given the morbidity and mortality of these operations, radiotherapy, chemotherapy, and immunotherapy are more often utilized. Although limited to case reports and small series, radical resection of the cavernous sinus has been proposed. We aimed to study surgeons' willingness to perform cavernous sinus exenteration (CSE) under different clinical scenarios. Design, Setting, Participants, Main Outcome Measures We conducted an online survey from April to July 2021 among members of the Skull Base Congress and the North American Skull Base Society. Descriptive statistics were used to analyze the main outcome measure of willingness to perform CSE . Results The analytic sample ( n = 112) included 54% otolaryngologists and 43% neurosurgeons. Eighty-six percent practiced in an academic setting. Surgeons' willingness to perform CSE was low (6-16% under different clinical scenarios), citing a belief that they could not obtain oncologic margins and the procedure's morbidity. Forty-five percent had at least one patient undergo CSE with 72% of patients surviving no more than 2 years. Complications included chronic intractable pain, cerebrospinal fluid leak, cerebrovascular accident, and/or intraoperative/postoperative death within 30 days. Sixty percent agreed that the availability of immunotherapy and genomic sequencing has affected their willingness to offer CSE. Conclusion Overall, most of the surgeons surveyed were unwilling to offer CSE for carcinomatous cavernous sinus invasion, whether for primary disease or recurrence. Given the rarity of these tumors and the limited data on CSE, these results may provide more information for clinicians and patients for these treatment decisions.

Pembrolizumab-combination therapy for previously untreated metastatic nonsquamous NSCLC: Real-world outcomes at US oncology practices.

The availability of immunotherapies has expanded the options for treating metastatic NSCLC, but information is needed regarding outcomes of immunotherapy for patients treated outside of clinical trials. The aim of this retrospective study was to evaluate the outcomes of therapy with first-line pembrolizumab plus pemetrexed and carboplatin (pembrolizumab-combination) for patients with metastatic nonsquamous NSCLC in the real-world setting of oncology clinics in the United States (US). Using deidentified, longitudinal patient records from a nationwide, electronic health record-derived US database, we identified patients with metastatic nonsquamous NSCLC, without EGFR/ALK/ROS1 genomic alterations, who had received no previous systemic anticancer therapy. Eligible patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 and initiated first-line pembrolizumab-combination therapy from 11-May-2017 to 31-January-2019; data cutoff was 31-August-2020. Patients treated in a clinical trial were excluded. Manual chart review supplemented technology-enabled abstraction to identify disease progression and tumor response. Time-to-event endpoints from initiation of pembrolizumab-combination therapy were determined using Kaplan-Meier. Of 377 patients with metastatic nonsquamous NSCLC, 105 (28%), 104 (28%), and 103 (27%) had programmed death-ligand 1 (PD-L1) expression ≥50%, 1-49%, and <1%, respectively; PD-L1 expression was not documented for 65 patients (17%). Median age was 66 years, and 227 patients (60%) were men. Median follow-up time from first-line therapy initiation to data cutoff was 31.2 months (range, 19.0-39.6 months). Median pembrolizumab real-world time on treatment (rwToT) was 5.8 months (95% CI, 5.0-6.7); 12- and 24-month on-treatment rates for pembrolizumab were 28.0% and 14.9%, respectively. Median overall survival (OS) was 17.2 months (95% CI, 13.6-19.9). For patients in PD-L1 expression ≥50%, 1-49%, <1%, and unknown cohorts, the 12-month survival rates were 66.0%, 58.5%, 54.5%, and 58.3%, respectively, and 24-month survival rates were 43.1%, 37.2%, 35.6%, and 42.0%, respectively. Median real-world progression-free survival was 6.2 months (95% CI, 5.5-7.1); and the real-world response rate was 39.3%, with median duration of response of 13.1 months (95% CI, 10.5-16.8). These findings demonstrate the benefits of first-line pembrolizumab-combination therapy for patients with EGFR/ALK-wild-type, metastatic nonsquamous NSCLC and good performance status who are treated at US community oncology clinics.

Minimal residual disease detection by next-generation sequencing in multiple myeloma: Promise and challenges for response-adapted therapy.

Assessment of minimal residual disease (MRD) is becoming a standard diagnostic tool for curable hematological malignancies such as chronic and acute myeloid leukemia. Multiple myeloma (MM) remains an incurable disease, as a major portion of patients even in complete response eventually relapse, suggesting that residual disease remains. Over the past decade, the treatment landscape of MM has radically changed with the introduction of new effective drugs and the availability of immunotherapy, including targeted antibodies and adoptive cell therapy. Therefore, conventional serological and morphological techniques have become suboptimal for the evaluation of depth of response. Recently, the International Myeloma Working Group (IMWG) introduced the definition of MRD negativity as the absence of clonal Plasma cells (PC) with a minimum sensitivity of <10−5 either by next-generation sequencing (NGS) using the LymphoSIGHT platform (Sequenta/Adaptative) or by next-generation flow cytometry (NGF) using EuroFlow approaches as the reference methods. While the definition of the LymphoSIGHT platform (Sequenta/Adaptive) as the standard method derives from its large use and validation in clinical studies on the prognostic value of NGS-based MRD, other commercially available options exist. Recently, the LymphoTrack assay has been evaluated in MM, demonstrating a sensitivity level of 10−5, hence qualifying as an alternative effective tool for MRD monitoring in MM. Here, we will review state-of-the-art methods for MRD assessment by NGS. We will summarize how MRD testing supports clinical trials as a useful tool in dynamic risk-adapted therapy. Finally, we will also discuss future promise and challenges of NGS-based MRD determination for clinical decision-making. In addition, we will present our real-life single-center experience with the commercially available NGS strategy LymphoTrack-MiSeq. Even with the limitation of a limited number of patients, our results confirm the LymphoTrack-MiSeq platform as a cost-effective, readily available, and standardized workflow with a sensitivity of 10−5. Our real-life data also confirm that achieving MRD negativity is an important prognostic factor in MM.

Patterns of care in Medicaid-enrollees with recurrent or metastatic cervical cancer.

e17525 Background: Cervical cancer remains a disease with high unmet need, and a large proportion of patients are insured through Medicaid (̃30%). Previous real-world studies demonstrated significant variability in treatments for recurrent or metastatic cervical cancer (r/mCC) patients following doublet chemotherapy ± bevacizumab, despite the 2018 approval of pembrolizumab in PD-L1+ r/mCC. As r/mCC treatment landscape continues to evolve, there is a need to understand current real-world unmet need among Medicaid r/mCC patients. This study aims to evaluate treatment patterns and healthcare resource utilization (HCRU) among Medicaid-insured r/mCC patients. Methods: This is a retrospective analysis of nationwide Medicaid claims to assess patient characteristics, treatment patterns, and HCRU among r/mCC patients between 2016-2019 (most recent Medicaid data available). First line treatment (1L) for r/mCC was identified as the first administration of systemic therapy without concomitant radiation or surgery. Patient characteristics, treatment patterns, and HCRU were characterized by line of therapy. Results: A total of 2,741 adult females initiated systemic treatment for r/mCC between 2016–2019, mean age was 52.8 (SD = 12.8), and most patients were enrolled in comprehensive managed care plans (58%). Over 41% (N = 1,145) had evidence of second line treatment (2L), with over one third (N = 385) of those also having evidence of third line treatment (3L). Consistent with treatment guidelines, the majority (61%) of 1L regimens were doublet chemotherapy ± bevacizumab. In contrast, no clear standard of care was observed among patients receiving 2L or 3L therapy. Notably, immunotherapy accounted for 22% of treatment regimens in 2L/3L overall, with its use increasing significantly over time (&lt; 6% in 2016 to 41% in 2019; p-value &lt; 0.001); however, despite availability of immunotherapy, most patients did not remain on treatment for a prolonged duration (immunotherapy median duration 2.2 months vs. 2.5 months for non-immunotherapy, p-value = 0.9). Across all HCRU measures (inpatient admissions, outpatient visits, emergency visits, and pharmacy claims), 2L/3L patients had less utilization per patient, compared with 1L patients. Conclusions: There was no clear standard of care for 2L+ r/mCC patients enrolled in Medicaid treated between 2016-2019. Although immunotherapy use is increasing, there is still high medical unmet need based on short durations of treatment and poor historical outcomes. New therapies should provide meaningful clinical benefit without significant increase in HCRU.

Disease management and frontline treatment of locally advanced or metastatic urothelial (la/mUC) carcinoma: The U.S. physician PARADIGM study.

456 Background: The treatment landscape for la/mUC is evolving. Data on current real-world treatment trends in la/mUC are limited. This study assessed US physician treatment decision-making and prescribing patterns using qualitative interviews (QIs). Methods: First, a targeted literature search (TLS) evaluated published abstracts from January 2018 to March 2021. Then, in July 2021, QIs with 15 US medical oncologists/urologists were conducted based on the TLS findings. Physicians were recruited for a 60-minute, 1-on-1 phone interview. Physicians had to be in practice ≥1 year post fellowship, a board-certified oncologist/urologist, and managed ≥1 la/mUC patients who received first-line (1L) systemic therapy in the past 6 months. Results: Seven published US retrospective studies found relatively low utilization of 1L systemic therapy with 40%-65% of la/mUC patients not treated; high attrition rates reported with only 15%-40% of 1L patients receiving second-line (2L) therapy. The TLS included patient data collected primarily through 2017 and did not capture current systemic treatment patterns for recently approved therapies. QI respondents were community oncologists (n = 8), academic oncologists (n = 4), and community urologists (n = 3). The average number of la/mUC patients seen in the past 6 months was 23 per physician. Physicians estimated that ≥75% la/mUC patients are currently being treated with systemic therapy, with all oncologists prescribing 1L immunotherapy (IO) maintenance to eligible patients (n = 10 prescribing avelumab for ≥90%). According to 11 respondents (73%), the proportion of systemic-treated patients has increased in recent years with the availability of IO and novel therapies. Top reasons for not prescribing systemic therapy were poor performance status (73%), old age (67%), patient preference (53%), and comorbidities (47%). Physician-reported 1L regimens administered were 41% carboplatin-based, 37% cisplatin-based, 17% single-agent IO, and 4% nonplatinum chemotherapy. Top criteria impacting 1L regimen choice were renal function (100%), performance status (75%), neuropathy (75%), and age (50%). IO was typically reserved for patients who were platinum ineligible or refused chemotherapy. Ten oncologists reported that 60%-80% of 1L la/mUC patients received a 2L treatment. Conclusions: From the QIs, physicians reported higher treatment rates compared to the TLS; however, our physician sample was small, and the TLS included patient data through 2017 and thus did not capture current systemic treatment patterns. Findings suggest that, over time, the proportion of US la/mUC patients treated with/eligible for 1L systemic therapy has increased, including IO maintenance, as well as for subsequent lines due to increased treatment options after 2017. A quantitative survey of 150 medical oncologists is planned next for this study.

Systemic therapy for recurrent and/or metastatic head and neck cancer: a population-based healthcare research study in Thuringia, Germany

PurposeSystemic therapy choice for patients with recurrent and/or metastatic head and neck cancer (R/M HNC) is a challenge. Not much is known about systemic therapies used in daily clinical routine and their outcome.MethodsData of all 283 patients with R/M HNC (89.4% male, median age: 60 years) registered for first-line systemic therapy between 2015 and 2018 in the cancer registries of Thuringia, a federal state in Germany, were included. Patient characteristics and treatment patterns were summarized. Exploratory univariate and multivariate analyses were conducted on select of systemic therapy and prognostic factors for overall survival.ResultsThe most frequent first-line regimens were platinum-based combinations (71.4%), mainly cetuximab + platinum + 5-fluorouracil (32.5%). 32.5, 13.1, 4.9, and 1.1%, respectively, received, a second, third, fourth, and fifth line of systemic therapy. Median follow-up was 5.5 months. Median real-world overall survival was 16.8 months [95% confidence interval (CI) 11.1–22.6]. Alcohol drinking [hazard ratio (HR) 2.375, CI 1.471–3.831; p < 0.001], no second-line therapy (HR 3.425, CI 2.082–5.635, p < 0.001), and application of three agents compared to one agent in first-line therapy (HR 2.798, CI 1.374–5.697; p = 0.005) were associated to decreased overall survival after start of first-line systemic therapy. Termination of second-line treatment because of deterioration of the general condition was the only independent negative prognostic factor (HR 4.202, CI 1.091–16.129; p = 0.037) after start of second-line systemic therapy.ConclusionsThis study offers useful information, mainly prior to the availability of immunotherapy, on patient characteristics, treatment patterns, and survival in a German real-world population.

476 Utilization and impact of immunotherapy in stage IV melanoma using the National Cancer Database

The majority of data regarding immunotherapy for melanoma stems from trials that exclude important populations. Thus, while trials may demonstrate favorable results, not all populations may be represented. To evaluate factors affecting the utilization of immunotherapy and to stratify results based on the approval of ipilimumab in 2011 and PD-1 inhibitors in 2014, an analysis of available data from the National Cancer Database (NCDB) was performed. Stage IV melanoma patients were identified. Effects of immunotherapy on overall survival (OS) were assessed using Kaplan Meier curves and Cox proportional hazards model. 19,233 patients were analyzed, of whom, 1,998 received immunotherapy. Between 2011-2013, and in 2014, 18.6% and 28.9% of patients received immunotherapy, respectively. Younger patients and those with fewer co-morbidities or receiving care in an academic institution were more likely to receive immunotherapy. Patients without insurance were less likely to receive immunotherapy. Patients who received immunotherapy from 2011-2013 had a 33% (95% CI 30-35%) 3-year OS compared to 23% (95% CI 21-24%) for those who did not. In 2014, 3-year OS was 37% (95% CI 32-43%) for those who received immunotherapy compared to 22% (95% CI 18-26%) for those who did not (log-rank p<0.0001). This is the first analysis of a large cancer database for patients with any cancer with stratification of results based on utilization and availability of immunotherapy. Immunotherapy utilization increased yearly and improved OS. With combination immunotherapy now more widely employed, it is expected these results will continue to improve.

Efficient Suppression of NRAS-Driven Melanoma by Co-Inhibition of ERK1/2 and ERK5 MAPK Pathways

Cutaneous melanoma is a highly malignant tumor typically driven by somatic mutation in the oncogenes BRAF or NRAS, leading to uncontrolled activation of the MEK/ERK MAPK pathway. Despite the availability of immunotherapy, MAPK pathway‒targeting regimens are still a valuable treatment option for BRAF-mutant melanoma. Unfortunately, patients with NRAS mutation do not benefit from such therapies owing to the lack of targetable BRAF mutations and a high degree of intrinsic and acquired resistance toward MEK inhibition. Here, we demonstrate that concomitant inhibition of ERK5 removes this constraint and effectively sensitizes NRAS-mutant melanoma cells for MAPK pathway‒targeting therapy. Using approved MEK inhibitors or a pharmacologic ERK inhibitor, we demonstrate that MAPK inhibition triggers a delayed activation of ERK5 through a PDGFR inhibitor-sensitive pathway in NRAS-mutant melanoma cells, resulting in sustained proliferation and survival. ERK5 phosphorylation also occurred naturally in NRAS-mutant melanoma cells and correlated with nuclear localization of its stem cell-associated effector KLF2. Importantly, MEK/ERK5 co-inhibition prevented long-term growth of human NRAS-mutant melanoma cells invitro and effectively repressed tumor progression in a xenotransplant mouse model. Our findings suggest MEK/ERK5 cotargeting as a potential treatment option for NRAS-mutant melanoma, which currently is not amenable for targeted therapies.

Real-world treatment patterns and clinical outcomes in advanced cutaneous melanoma patients in France.

Since 2011, the management of advanced melanoma has radically changed with the availability of new therapies (immunotherapy and BRAF-targeted therapy) and with BRAF testing. Following the introduction of these new therapies, the objectives of this AMEL study were to describe treatment patterns and evaluate overall survival (OS) among unresectable stage III/IV melanoma patients, in a real-life setting in France. The AMEL study is a multicentre retrospective record review study. Thirty-three physicians working in 33 unique treatment centres participated in the study. Two hundred and sixty-four patients diagnosed between 1 January 2012 and 31 October 2012 with unresectable stage III/IV melanoma were included in the study. 94.7% of the patients received a first-line antitumour drug treatment, 62.5% a second-line treatment while 26.9% received a third-line treatment with no significant differences between patients with a BRAF mutation (50.4%) and BRAF wild type (47.0%). First-line treatment differs according to the BRAF status: 74.8% of patients with a BRAF mutation received a BRAF inhibitor while 79.3% of the BRAF wild-type patients were treated with conventional chemotherapy. In second line and over, the treatment patterns were more heterogeneous, depending on the BRAF mutation, the treatment received previously, the speed of progression of the disease and the availability of immunotherapy at the time the treatment was initiated. Regardless of the BRAF mutation status, the median OS of patients was 16months (95% CI=14-18). Compared to a similar study conducted in 2007 (MELODY), a gain of 4months is observed. The gain seems to be higher for patients with a BRAF mutation (18months) than for those without a BRAF mutation (14months). The OS of patients who sequentially received both a BRAF inhibitor and ipilimumab (28months) highlights the benefit of this treatment sequence.

PP13.1 – 2834: Paediatric anti-N-methyl-D-aspartate receptor encephalitis: The first Italian multicenter case series

Objective Given the rarity of this condition, especially in children, there is a paucity of literature reporting large case series of paediatric anti-N-methyl-D-aspartate receptor encephalitis. Our goal is to contribute to define the features of paediatric anti-N-methyl-D-aspartate receptor encephalitis. Methods We describe a new nationwide case series of 20 children (50% females), referred by 13 Italian centers. Results Mean age at onset was 8 years (range 3–17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioral/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12–18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. Most patients recovered substantially (80%); this rate was higher among older patients, and in those receiving first immune therapy within 1 month. Conclusion Our case series confirms a symptomatologic core of paediatric anti-N-methyl-D-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of the patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. Paediatricians should consider this diagnosis for children presenting with neurological and/or behavioral or psychiatric disturbances, regardless of age and gender, especially in the absence of data suggesting other specific etiologies. Other authors: F. Beccaria, L. Giunta, C. Boniver, M.G. Natali Sora, N. Zamponi.

Paediatric anti-N-methyl-D-aspartate receptor encephalitis: The first Italian multicenter case series.

Given the rarity of this condition, especially in children, there is a paucity of large reported paediatric case series of anti-N-methyl-d-aspartate receptor encephalitis. To contribute to define the features of this condition, we describe retrospectively a new nationwide case series of 20 children (50% females), referred by 13 Italian centres. Mean age at onset was 8 years (range 3-17). Prodromal symptoms were reported in 31.6%; onset was with neurological symptoms in 70%, and with behavioural/psychiatric disturbances in 30%. Most patients developed a severe clinical picture (90%), and 41% experienced medical complications; children 12-18 years old seemed to be more severe and symptomatic than younger patients. All children received first-line immune therapy; second-line treatment was administered to 45%. Relapses occurred in 15%. At last follow-up (mean 23.9 months, range 5-82), 85% patients had mRS 0-1; this rate was higher among older patients, and in those receiving first immune therapy within 1 month. Our case series confirms a symptomatologic core of paediatric anti-N-methyl-d-aspartate receptor encephalitis, even though displaying some distinctive features that may be explained by a specific genetic background or by the limited number of patients. The growing incidence of this condition, the relative age-dependent variability of its manifestations, the availability of immunotherapy and the possible better outcome with early treatment impose a high index of clinical suspicion be maintained. In the absence of data suggesting other specific etiologies, paediatricians should consider this diagnosis for children presenting with neurological and/or behavioural or psychiatric disturbances, regardless of age and gender.