Participants received a single 25-mg dose of synthetic psilocybin in conjunction with psychological support. The primary aim was to assess safety, tolerability and feasibility at post-treatment by incidences and occurrences of adverse events (AEs) and clinically significant changes in electrocardiogram (ECG), laboratory tests, vital signs and suicidality. No clinically significant changes were observed in ECG, vital signs or suicidality. Two participants developed asymptomatic hypoglycemia at post-treatment, which resolved within 24 h. No other clinically significant changes were observed in laboratory values. All AEs were mild and transient in nature. Participants’ qualitative perceptions suggest that the treatment was acceptable for most participants. Results suggest that psilocybin therapy is safe, tolerable and acceptable for female AN, which is a promising finding given physiological dangers and problems with treatment engagement. ClinicalTrials.gov identifier NCT04661514.Anorexia nervosa (AN) is a deadly illness with no proven treatments to reverse core symptoms and no medications approved by the US Food and Drug Administration. Novel treatments are urgently needed to improve clinical outcomes. In this open-label feasibility study, 10 adult female participants (mean body mass index 19.7 kg m Phase 1 trial results demonstrate that psilocybin in conjunction with psychological support is safe, tolerable and deemed acceptable and therapeutically meaningful by female individuals with anorexia nervosa. It is associated with substantial morbidity and mortality, including an elevated suicide rate and an 18-fold increase in mortality3. Despite its seriousness, there are no proven treatments for adult AN that reverse core symptoms and no approved pharmacological interventions1. As a result, estimates suggest that less than half of patients achieve recovery; relapse rates approach 50%; and approximately 20% of those with AN will develop a chronic course3. There have been minimal advancements in novel treatment strategies and stagnant outcomes over the past several decades, resulting in a ‘crisis in care’5. Novel and innovative treatments methods are urgently needed to improve treatment engagement and outcomes. One such avenue may be psilocybin therapy.Anorexia nervosa (AN) is a costly and deadly mental illness, which is notoriously difficult to treat2A)6 and is the main psychoactive compound in the Psilocybe genus of mushrooms7. Considerable evidence suggests that individuals with AN have altered brain serotonin (5-HT) function, altered function of the 5-HT2A receptor and altered endogenous brain 5-HT secretion9, supporting the speculation that the 5-HT2A effects of psilocybin might effect change in AN symptoms. Unlike other serotonergic medications requiring repeated administrations, a single dose of psilocybin may lead to rapid and enduring synaptic adaptations that have the potential to improve AN symptoms10. However, the role of 5-HT dysfunction in AN and related affective states associated with restriction remains poorly understood with mixed findings12.Psilocybin is a psychedelic molecule whose mechanism of action is thought to be mediated by serotonin 2A -related preoccupations, rigid thinking styles and entrenched behavioral patterns24. AN is often ego-syntonic in nature25, and AN behaviors are perceived as effective means to achieve internalized weight/shape ideals and avoid dysphoric mood states that result from eating9. Thus, individuals with AN may resist intervention or fail to acknowledge the seriousness of the illness, resulting in low treatment acceptability and substantial treatment dropout26. Psilocybin therapy, which has been shown to improve openness27 and occasion transformative experiences17, may facilitate a re-organization of values, shifting the relative importance of shape and weight and/or induce greater permeability to new attitudes and behaviors by directly targeting these features. Previous observational and naturalistic studies exploring the value of psilocybin and other psychedelic drugs in people with EDs have reported on emerging themes, such as increased affective and intellectual awareness, reduction in ED symptoms, positive mood changes, emotional processing and increases in self-acceptance30.AN is characterized by excessive and undue preoccupation, fear and distress surrounding food, weight, shape and eating. This typically leads to rigid and repetitive behavioral patterns of control, such as restrictionNCT04505189 and NCT04052568), and other ED expert groups have provided rationales for further evaluation of psychedelic treatments for AN32.To date, no modern publications have reported data regarding the safety, tolerability and efficacy of psilocybin therapy for AN within the context of a clinical intervention; however, at the time of this publication, two additional registered clinical trials are currently underway  or through community providers familiar with the study through community outreach efforts , and no suicidal behaviors were present in the post-dosing follow-up visits. One participant with a history of major depressive disorder (MDD) and SI reported an increase in SI at 3-month follow-up, which did not appear related to study participation. AEs , clinical laboratory tests and suicidality from baseline (day −1) to day 1 Table  and 1-weEs Table  were milt-tests indicated that weight concerns decreased significantly from baseline (day −1) to 1-month  and 3-month  follow-up, with a medium to large effect. Shape concerns significantly decreased at 1-month follow-up  but were no longer significant at 3-month follow-up . Changes on the eating concern and dietary restraint subscales were not significant, but changes in eating concerns approached significance at 3-month follow-up . Effects of treatment were, however, highly variable among participants, as is illustrated from the case series data  subscales are shown in Table ine day − to 1-mon−2).On average, changes in body mass index (BMI) were not statistically significant , trait anxiety (Spielberger State-Trait Anxiety Inventory (STAI-T))  and preoccupations and rituals surrounding food, eating and shape )  )  questionnaire is reported in Extended Data Fig. t-tests indicated that functional impairment related to disordered eating as measured by the CIA decreased significantly from baseline (day −1) to 1 month . Other changes measured were not statistically significant.We also explored changes in depression scores (Quick Inventory of Depressive Symptomatology (QIDS)), functional impairment related to ED psychopathology ) and readiness and motivation to change (Readiness Motivation Questionnaire (RMQ)) at 1-month follow-up. Results are presented in Extended Data Table 35. Additionally, pAN has been shown to be common, severe, persistent and undertreated35.To our knowledge, this is the first data report on the effects of psilocybin therapy in AN in a clinical research trial. This open-label pilot study examined the safety and tolerability of administering psilocybin therapy to participants with AN and pAN. We chose to include participants in partial remission because we were most interested in exploring potential changes in core ED psychopathology (versus weight), which can lead to treatment resistance and which can persist after weight restorationPsilocybin therapy, which includes psychological support by trained therapists, was found to be safe and well tolerated for the 10 participants who received treatment in this study. Most participants endorsed the treatment as highly meaningful and the experience as a positive life impact, and yet effects on ED psychopathology were highly variable, with a subset of participants demonstrating a robust response for a single-dose treatment. Results of this study are preliminary and inconclusive given its size and design. In this section, we discuss study findings related to primary outcomes, patient acceptability and qualitative perceptions as well as ED-specific psychopathology.36. The incidence of hypoglycemia is clinically important and may indicate that attention to blood glucose levels before and after intervention may be warranted in participants with compromised nutritional status given the dangers associated with hypoglycemia in AN, including sudden death36. Both incidents of hypoglycemia occurred in participants who were given a standardized breakfast upon arrival. AN has a high prevalence of serious medical complications and physiological disturbances, which account for much illness-related death. The lack of negative incidences regarding safety in our study is promising for future research with the AN population; however, larger studies with a more diverse participant group continue to be needed to determine safety37.No participants in our study experienced any serious AEs, and all treatment-emergent AEs resolved within 24 h and without intervention (with the exception of one report of orthostatic heart rate that was reported at 3-month follow-up for one participant). Hypoglycemia occurred in two participants on the dosing day and resolved in 24 h. We hypothesize that this was related to a prolonged period of fasting on the dosing day (a common effect of psilocybin) versus any direct relationship to the drug, given the state of malnutrition and low carbohydrate stores associated with AN. Food was available on request to participants during the dosing day, but participants were not required to eat during the therapeutic experience. To our knowledge, there are no reports of psilocybin-induced hypogylcemia. However, individuals with AN often have reduced plasma glucose levels38. Positive patient perceptions are also notable because they may suggest improved quality of life, which is clinically important for those with a potentially severe and enduring illness38. These self-reported data suggest that most participants perceived some benefit that may have been ED-non-specific in nature or not well captured by our assessment measures. Although our treatment included AN-specific therapeutic elements, adjunctive therapy was brief. Additional therapeutic methods, or extended therapeutic time, may be a useful consideration to facilitate further behavioral change and increased specificity, as has been employed in other psilocybin studies40. Our effect sizes and response rates were less robust than those reported for primary outcomes in psilocybin studies for other psychiatric disorders43. This may also be related to a heterogenous sample, a single-dose trial (compared to a two-dose design used in other studies), a lack of sensitivity in assessment measures or unique/specific features of AN that are not as readily addressed by psilocybin therapy or that require dosing adjustments. AN is a difficult-to-treat disorder with a complex physiology and physical recovery needs that differentiate it from other mental illnesses. Notably, 90% of participants reported that one dosing session was not enough, suggesting that an additional psilocybin experience(s) may be beneficial44.Most participants self-reported positive changes 3 months after the psilocybin dosing. That the treatment was regarded as beneficial by most participants and that there were no dropouts are promising signs of engagement. Dropout rates in currently available treatments tend to be high34 in ED psychopathology (EDE) at 3-month follow-up, with scores decreasing from clinical ranges to within 1 s.d. of community normative values34. Within the responder group, ED psychopathology decreased precipitously and dropped below clinical levels within the month after the psilocybin dosing session. Three of the responders were not enrolled in any concurrent mental health services during the study period but had mental health treatment histories, and one was in longstanding, outpatient therapy that did not change during study enrollment. Symptoms continued to improve between 1-month and 3-month follow-up. Given the size and design of this study, these effects are preliminary and inconclusive. However, it is notable that we found such a robust response in a subset of participants in a single-dose trial of psilocybin delivered over a brief time period, because currently available treatments for adult AN result in only modest improvements in symptoms and often focus on weight and nutritional rehabilitation without adequately addressing underlying psychopathology38. Participants also experienced significant reductions in anxiety; however, mean changes in depression scores were not significant. Changes in general psychopathology may partially explain the effects on ED symptoms44.Our exploratory analysis showed some significant reductions in ED-related psychopathology when the sample was aggregated; however, the results were highly variable among participants. Forty percent (4/10) of participants demonstrated clinically significant reductions46. Notably, there are well-documented phenomena associated with AN that impede upon weight rehabilitation, including hypermetabolism and unusually high caloric requirements37. When queried about the lack of weight change, one treatment responder stated, ‘The irony is that now that I want to recover I can eat intuitively, but that is not enough to support physical recovery’. These findings may suggest that targeted nutritional rehabilitation emblematic of traditional treatment may be a necessary adjunctive treatment even when significant improvements in ED psychopathology are conferred.We did not observe a significant effect on BMI over time, and results were highly variable among participants. BMI did not follow the same change trajectory as ED psychopathology for participants who showed reductions on core psychopathology. Of the four treatment responders, two showed positive BMI trends, one remained stable at a normal BMI and one showed a two-point decrease over time. It is also possible that a longer follow-up period is necessary to observe meaningful changes in BMI, which has been suggested by ED expertsLimitations of this study include its small sample size, the lack of a control comparison and the open-label design. Owing to the exploratory nature of this study, we did not conduct a power analysis or correct for multiple comparisons. As a result, these findings are not conclusive and should be interpreted with caution. Additionally, all of the participants were self-referred, which may have resulted in a selection bias. Similarly, suggestibility and expectations of positive outcomes related to positive popular media coverage surrounding psychedelics, and attending treatment at a well-reputed ED service , may have resulted in a suggestibility that influenced positive outcomes. Our sample included a diverse range of severity; however, many participants had mild to moderate AN. More research is needed to evaluate psilocybin therapy for severe presentations. The study also lacked gender, racial and cultural diversity.Strengths of this study included administration of a precise dose of pure synthesized psilocybin and the evaluation of a highly novel treatment modality for a treatment-resistant population. Larger, adequately powered, well-controlled trials with comparator treatments are needed to evaluate the efficacy of psilocybin therapy in a diverse sample of patients with AN. Future studies should further investigate mechanisms of action and moderators of treatment to discern how psilocybin may lead to changes in AN and whether psilocybin therapy is more suitable and effective for a specific subset of AN. Additionally, future studies are needed for optimization to identify adequate dosage, identify the optimal number of psilocybin administrations and investigate the need for possible adjunctive treatments that could optimize treatment outcomes.In conclusion, results from this open-label, single-arm study suggest that psilocybin therapy is safe and tolerable in participants with AN; however, adequately powered, randomized controlled trials are needed to draw any conclusions.Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) criteria for AN (anorexia nervosa restricting (AN-R) and AN-BP subtypes) within a current episode or in partial remission. All participants received a 25-mg dose of investigational drug COMP360, a proprietary pharmaceutical-grade synthetic psilocybin formulation, optimized for stability and purity, developed by COMPASS Pathfinder Ltd. administered in conjunction with psychological support. The inclusion criteria were a current diagnosis of AN or pAN and an age range of 18–40 years. No financial compensation was provided for participation. Medical exclusion criteria included BMI < 16 kg m−2, medical instability, positive pregnancy test, cardiovascular conditions within the last year and any other clinically significant illnesses or disturbances of physical systems. Psychiatric exclusions included a current or previously diagnosed psychotic disorder, substantial suicide risk, substance use disorder (within the last year), history of mania and positive screening for borderline personality disorder (McLean Screening Instrument). Demographics are reported in Table This open-label pilot study evaluated the safety, tolerability and preliminary efficacy of psilocybin therapy for participants with AN. Participants were 10 female adults who met current 48. Thus, it is challenging to recruit males. The vast majority of those who expressed interest in this study were female , and all participants were identified females by self-report.Study information was posted on ClinicalTrials.gov and advertised through the Eating Disorder Treatment & Research Center at the University of California, San Diego (UCSD). The trial was approved by the US Food and Drug Administration, the Regulatory Approval Committee of California and the UCSD Institutional Review Board . All participants provided written informed consent to the study team personnel at the start of the in-person screening visit. It is well known that AN is more prevalent and more often diagnosed in females49. A DEA Form 223 license was obtained by the principal investigator (PI) for storage and dispensing authorization. Screening included review of informed consent and written signature and medical screening, including an ECG, blood tests, assessment of vitals and review of past medical records. This also included a psychiatric interview, and assessment, including the Mini-International Neuropsychiatric Interview 7.0.2 (MINI)50, to ascertain a diagnosis of AN and rule out a current or past psychotic disorder, bipolar disorder and history of mania was completed. Other psychiatric screening assessments included imminent suicidality within the past year (C-SSRS)33, the McClean Screening Instrument for Borderline Personality Disorder51 and an interview informed by DSM-5 criteria to rule out substance use disorders within the past year. Ten eligible participants were included in the study, including three participants from outside of the southern California region who received partial study funding for relocation expenses. Participants did not enroll/change mental health treatment during study screening and enrollment. One participant received concurrent treatment at a partial hospitalization program commencing at the onset of screening. Five participants continued to participate in ongoing weekly outpatient therapy services that did not change during study enrollment.The study investigational drug was COMP360, a proprietary pharmaceutical-grade synthetic psilocybin formulation, optimized for stability and purity, developed by COMPASS Pathfinder Ltd. (five capsules of 5 mg of psilocybin)The study team reviewed the results of the screening to determine eligibility. Eligible participants who were on serotonergic medications were titrated off these medications over the screening period. During this ‘washout period’, they met with the study PI, who monitored titration and assessed response, and a clinical psychologist, who conducted a suicide assessment (C-SSRS) weekly throughout the screening period. Baseline assessments were conducted the day before the psilocybin session day −1) , during which they completed post-treatment repeated assessments and met the study psychologists for a safety assessment and a 60–90-min integration session . Participants then returned to the clinic for continued assessment at 1-week, 1-month and 3-month follow-up. Participants also received two integration sessions at day 1 and day 7. The 3-month follow-up visit was conducted via telehealth for seven participants owing to change in location.n = 10 participants). The primary measure for exploring effects of the treatment on ED symptoms and behaviors was the EDE53. We explored sample mean changes in ED symptoms and behaviors, including weight concerns, shape concerns, eating concerns and dietary restraint at 1 month and 3 months after the dosing session.The main objective of this study was to evaluate the safety and tolerability of psilocybin therapy for AN. To this end, the primary outcome measures were reports of AEs, changes in vital signs, ECGs, clinically significant changes in clinical laboratory tests and suicidality. These features were assessed in all 10 participants the day before the dosing session (day −1), after the dosing session (day 1) and at 1-week follow-up to evaluate any changes. We also assessed pre-specified secondary measures of response to the treatment and preliminary treatment efficacy by exploring changes in ED symptoms and behaviors and related psychopathology , and the Eating Disorders Inventory (EDI)55. Additionally, we assessed changes in features that can characterize AN, including BMI, body image (PASTAS)56, Body Image State Scales (BISS)57, state and trait anxiety (STAI-T)58 and preoccupation and rituals related to eating, food, weight and shape (YBC-EDS)59 (n = 10 participants).We were primarily interested in changes in the EDE because it is designed to assess the full range of specific psychopathology related to EDs and is considered the gold standard measurement60, depressive symptoms (Quick Inventory of Depressive Symptomatology-Self Report (QIDS-SR))62, readiness toward actionable change (Readiness and Motivation Questionnaire)62, psychedelic intensity ratings (5D-ASC)52 and patient acceptability. The primary endpoint for all psychological measures was 1-month follow-up. We also repeated measures at 3-month follow-up. At 3-month follow-up, patient acceptability was evaluated by asking participants qualitative yes/no questions about the effect of their experience on life and well-being, some of which were developed by Griffiths et al.63.Pre-specified exploratory outcomes included assessing for changes in ED-related functional impairment (CIA)t-tests . All data were collected using Qualtrics . Data were analyzed using SAS analytic software version 9.4 We also present individual participant changes in the EDE and BMI 64 at 1-month and 3-month follow-up using a case series design. Owing to the small sample size for this initial pilot study, we have also included effect sizes using Cohen’s d values. Multiple a priori comparisons were explored for this study; however, owing to its exploratory nature, we chose not to use a correction accounting for multiple comparisons.Owing to the exploratory nature of this study, we did not perform a power analysis. Ten participants were studied to provide an initial impression of safety, tolerability, acceptability and efficacy of this treatment in an effort to inform future trials. In this report, we summarize the results of 10 participants by presenting incidences of AEs and incidences of significant changes in our safety measures  at day 1 and 1-week follow-up. To explore initial efficacy, we evaluated mean sample changes in secondary outcome measures at 1-month follow-up using paired Further information on research design is available in the Any methods, additional references, Nature Portfolio reporting summaries, source data, extended data, supplementary information, acknowledgements, peer review information; details of author contributions and competing interests; and statements of data and code availability are available at 10.1038/s41591-023-02455-9.Reporting SummarySource Data Fig. 2Unidentified prescreen and screen information.Source Data Extended Data Fig. 1Global EDE scores at timepoints: day −1, day 28 and day 84.Source Data Extended Data Fig. 2Global EDE scores at timepoints: day −1, day 28 and day 84  noted on spreadsheet).Source Data Extended Data Fig. 3Participant subscale scores for 5D-ASC questionnaire.Source Data Extended Data Table 2Baseline (day −1) and day 28 (1 month) participant scores for EDE-QS, EDI, YBC-EDS and BMI assessments.Source Data Extended Data Table 4Baseline (day −1) and day 28 (1 month) participant scores for PASTAS-trait, PASTAS-state, STAI-state, STAI-trait and BISS.Source Data Extended Data Table 5Baseline (day −1) and day 28 (1 month) participant scores for CIA, QIDS and RMQ Action.


Limited access to specialized palliative care exposes persons with late-stage Alzheimer’s disease and related dementias (ADRD) to burdensome treatment and unnecessary hospitalization and their caregivers to avoidable strain and financial burden. Addressing this unmet need, the purpose of this study was to conduct a randomized clinical trial (RCT) of the ADRD-Palliative Care (ADRD-PC) program.N = 424 dyads of hospitalized patients with late-stage ADRD with their family caregivers. Intervention dyads will receive the ADRD-PC program of (1) dementia-specific palliative care, (2) standardized caregiver education, and (3) transitional care. Control dyads will receive publicly available educational material on dementia caregiving. Outcomes will be measured at 30 days (interim) and 60 days post-discharge. The primary outcome will be 60-day hospital transfers, defined as visits to an emergency department or hospitalization ascertained from health record reviews and caregiver interviews (aim 1). Secondary patient-centered outcomes, ascertained from 30- and 60-day health record reviews and caregiver telephone interviews, will be symptom treatment, symptom control, use of community palliative care or hospice, and new nursing home transitions (aim 2). Secondary caregiver-centered outcomes will be communication about prognosis and goals of care, shared decision-making about hospitalization and other treatments, and caregiver distress (aim 3). Analyses will use intention-to-treat, and pre-specified exploratory analyses will examine the effects of sex as a biologic variable and the GDS stage.The study will use a multisite, RCT design and will be set in five geographically diverse US hospitals. Lead investigators and outcome assessors will be masked. The study will use 1:1 randomization of patient-caregiver dyads, and sites will enroll The study results will determine the efficacy of an intervention that addresses the extraordinary public health impact of late-stage ADRD and suffering due to symptom distress, burdensome treatments, and caregiver strain. While many caregivers prioritize comfort in late-stage ADRD, shared decision-making is rare. Hospitalization creates an opportunity for dementia-specific palliative care, and the study findings will inform care redesign to advance comprehensive dementia-specific palliative care plus transitional care.ClinicalTrials.gov NCT04948866. Registered on July 2, 2021.The online version contains supplementary material available at 10.1186/s13063-023-07614-4. Alzheimer’s disease and related dementias (ADRD) affect 6.5 million Americans and their family caregivers : three mPersons with late-stage ADRD suffer progressive dependency and distressing symptoms. Late-stage ADRD, defined as Global Deterioration Scale (GDS) 5–7, is characterized by moderately severe to very severe cognitive impairment and the need for daily caregiver support for activities of daily living (ADLs) –8. NeuroCaregivers of persons with late-stage ADRD experience physical, emotional, and financial strain –13. CarePersons with late-stage ADRD are frequently hospitalized , 16, andIn prior research, caregivers of persons with late-stage ADRD prioritized the goal of comfort over life prolongation , 25. ForAcute illness is a sentinel event in ADRD, signaling an important opportunity to access palliative care teams, which are present in 72% of US hospitals –34. Compp < 0.001) and to make a decision to avoid future hospitalization  [p < 0.001, range 0–10), with increased symptom management for dyspnea , constipation , depression , and delirium  [p < 0.001) and goals of care  [Building on Alzheimer’s Association Practice Recommendations , the Adv= 0.033) . With AD< 0.001) . Moreove< 0.001) .Fig. 1AlAim 1: To conduct a multi-site RCT of the ADRD-PC program (intervention arm) vs publicly available educational material for dementia caregivers (control arm) to compare 60-day hospital transfers  for persons with late-stage ADRD (primary outcome). H1: 60-day hospital transfers will be lower in the intervention vs control arm.Aim 2: To compare patient-centered secondary outcomes between the intervention and control arms: (a) symptom treatment , (b) syAim 3: To compare caregiver-centered secondary outcomes between the intervention and control arms: (a) communication about prognosis and goals of care, (b) shared decision-making, and (c) caregiver distress . CaregiOur research objective is to conduct a multi-site efficacy randomized clinical trial (RCT) of the ADRD-PC program. We will enroll 424 dyads of hospitalized patients with late-stage ADRD (GDS 6–7 or GDS 5 with significant co-morbidity) with their family caregivers at 5 geographically diverse sites in the USA. Our primary hypothesis is that ADRD-PC will reduce hospital transfers (aim 1). The specific aims are as follows:The design is an RCT conforming to SPIRIT and CONSORT statements for trial methods and protocol , 54. TheThe study setting will be five US medical centers with interdisciplinary palliative care teams: University of North Carolina at Chapel Hill Medical Center (UNC), Massachusetts General Hospital/Harvard Medical School (MGH), Indiana University Health University Hospital (IU), UCHealth University of Colorado Hospital (UC), and Emory University Healthcare System (EU). Study sites are members of the Palliative Care Research Cooperative (PCRC) and utilize the Epic electronic health record system. Sites were recruited by a standardized PCRC process that seeks clinical trial sites with study-specific clinical practice resources matched to trial recruitment needs.Before enrollment of study participants, the principal investigator (PI) and project manager will provide consultation for site-based teams to incorporate ADRD-PC tools in hospital electronic health records (EHR) systems. New tools will include the screening/case finding algorithm, the template for documenting clinical encounters, and the template for the Palliative Care Plan at discharge. The PI, project manager, and clinical research coordinator (CRC) will provide 4 h of research protocol training for site clinical research coordinators (site-CRCs) and site principal investigators (site-PIs) . The proThe study will enroll 424 dyads of hospitalized persons with late-stage ADRD and their family caregivers; dyads will participate for 60 days following the index hospitalization. The eligibility criteria for persons with ADRD are (1) aged 55 or older, (2) hospitalized, (3) have a physician-confirmed diagnosis of ADRD, and (4) staged GDS 6 or 7 or GDS 5 with additional co-morbidity defined by Charlson Comorbidity Index scored > 5. As in the pilot, the ADRD stage will be confirmed by the attending physician and caregiver. The eligibility criteria for caregivers are (1) the adult (aged 18 or older) legally authorized representative (LAR) for healthcare and has the capacity to serve in this role, (2) support the person with ADRD, and (3) can complete interviews in English. As in our prior ADRD research, other family caregivers may be present per primary caregiver request, but only the primary caregiver is a participant. Dyads will be excluded if (1) the LAR is not a family caregiver, (2) the patient currently receives palliative care or hospice, or (3) patient or caregiver would be unduly stressed.To recruit study participants, the site-CRCs will use rapid case-finding methods from the ADRD-PC pilot RCT, reviewing the lists generated by EHR screening algorithms to identify persons aged 55 and older with ADRD within 24 h of hospitalization . After aFamily caregivers may be present in the hospital, barred from visitation due to COVID-19 restrictions and safety concerns, or may live at a great distance from the hospital; thus, recruitment and enrollment procedures will include both in-person and telephone/virtual communication methods.Site-CRCs will introduce the study to eligible family caregivers using scripted telephone calls or in-person visits. When the site-CRC conducts recruitment and enrollment via telephone, he or she will ask if the individual is in a private location and feels comfortable talking about the study at that time. The site-CRC will schedule an alternative time if necessary.The family caregiver will provide informed consent for themselves and for all persons with ADRD as they lack decisional capacity. If the family caregiver chooses to participate, the site-CRC will conduct the informed consent interview in person or over the phone. If the family caregiver agrees to participate, study informational materials and the informed consent form will be sent to them by mail or secure e-mail. Due to the low risk of study participation and the restrictions on immediate written consent described above, verbal consent will be accepted for participation in the enrollment caregiver interview and for randomization with initiation of the ADRD-PC or control conditions.Not applicable as no additional consent provisions for ancillary studies are included.Randomization will occur following the enrollment interview, with the dyad as the unit of randomization and analysis. To ensure concealed allocation of randomization, the study statistician will create site-specific, computer-generated random treatment assignments to assign dyads in a 1:1 ratio to intervention or control arms.The randomization will be generated by the study statistician within the REDCap software and will remain concealed until the evaluation of the study aims .After the allocation sequence is generated, each patient/caregiver dyad will be assigned a study ID number in each site. The site-CRC will reveal allocation to the site-PIs, who will communicate study arm assignment to the attending physician and to the palliative care team to initiate ADRD-PC consultation (intervention), or site-CRCs will deliver a copy of publicly available dementia caregiver educational material (control).Patient-caregiver dyads that are randomized to the intervention will receive the ADRD-PC program that includes speciality palliative care consultation during hospitalization and telephone-based transitional care over 2 weeks after discharge. ADRD-PC dementia-specific palliative care, standardized caregiver education, and transitional care are described below.Members of the site-based, interdisciplinary palliative care team, including a physician or advanced practice provider and at least one additional discipline , will visit the dyad in the hospital until hospital discharge. Palliative care clinicians will address four domains: (1) prognosis—exploration and communication of stage, trajectory, and prognostic awareness; (2) symptoms—assessment and treatment for physical and neuropsychiatric symptoms; (3) shared decision-making—exploration of values and goals of care and discussion of treatment decisions; and (4) transitional care—assessment of needs, care planning, and recommendation for support services. Discussions may include exploration of the overall goals of care and decision-making about potentially burdensome treatments of resuscitation, ventilator use, feeding tubes, antibiotics, or future hospitalizations. When clinically appropriate, consultation will also include the completion of new advance directives, such as a Physician Orders for Life-Sustaining Treatment (POLST) , or compMembers of the site-based, interdisciplinary palliative care team will share and discuss the booklet, “Advanced Dementia: A Guide for Families,” which addresses common concerns and treatment decisions . In discMembers of the site-based, interdisciplinary palliative care team will also provide transitional care at three time points . Pre-disPatient-family caregiver dyads randomized to the control arm will receive educational materials from the Alzheimer’s Association, specifically designed for late-stage ADRD caregivers, delivered by the site-CRCs . The patAs described in Table The PI will review monthly tracking reports of fidelity metrics and will use teleconferences to provide monthly coaching calls to site-CRCs, site-PIs, and clinicians. Coaching will be tailored and may include a review of study procedures, feedback on enrollment, retention and fidelity data, and strategies to overcome barriers. Sites failing to meet fidelity will be given site-specific feedback and re-training.The lead investigator, a co-investigator (MT), a study consultant (SM), and outcome assessors will be masked. They will remain masked to the study arm assignments until analysis; however, site-PIs, including one study co-investigator (CK), and the study statistician (FCL) will not be masked due to their roles in communicating study arm assignments and adverse event reporting. Site-CRCs will be masked to the study arm to collect outcome measures in family caregiver interviews. Since the EHR in study sites will have data regarding ADRD-PC palliative care encounters, site-CRCs will complete follow-up EHR reviews after 60-day follow-up interviews are completed and study participation ends for each dyad.If an unanticipated serious adverse event occurs, the IRB and the DSMB will consider unblinding prior to the final analyses if judged necessary to address participant safety.The description of study outcomes, measures and method of aggregation, data sources, and timing of data collection are reported in Table Secondary patient outcomes will include (1) symptom treatment as measured by Palliative Care Domain Index items , which hSecondary caregiver outcomes will include (1) documented discussion of dementia prognosis as measured by the percentage of caregivers with documented discussion of dementia prognosis during the index hospitalization; 2) documented discussion of goals of care as measured by the percentage of caregivers with documented discussion of goals of care during the index hospitalization; (3) shared decision-making regarding hospitalization as measured by the percentage of caregivers reporting shared decision-making about future hospitalization; (4) shared decision-making regarding burdensome treatment as measured by the percentage of caregivers reporting shared decision-making about resuscitation, ventilator use, tube feeding, and antibiotics for infection treatment; (5) caregiver distress as measured by the Family Distress in Advanced Dementia Scale , which r documentr 0.62–0.79) [In addition to these outcomes, data on covariates will be collected through EHR review and interviews with family caregivers. Patient demographics will include age, sex, race and ethnicity, and marital status. The pre-admission residence will be measured as a private home, assisted living facility, nursing home, or others. Patient co-morbidity will be measured using the Charlson Comorbidity Index, a validated, widely used index with weighted scores for age and diagnoses . Functio62–0.79) . ADRD st62–0.79) . Advance62–0.79) . Surviva62–0.79) . Family Participant flow is shown in Table N = 424 dyads of hospitalized patients with late-stage ADRD (GDS 6–7 or GDS 5 with significant co-morbidity) with their family caregivers. Statistical power is based on a 2-sided alpha of 0.05 significant tests and using standard deviation estimates from our pilot study (Table n = 180 per group at 60-day follow-up) and a “worst case” 25% dropout rate (n = 159 per group). These rates consider 9% patient mortality and 92% caregiver retention rate in the pilot. In our pilot data, 0.52 is the lower bound of the 95% confidence interval for the incidence rate ratio (IRR) comparing intervention vs control for 60-day hospital transfers. This corresponds to an average absolute reduction of 0.26 transfers per 60-day period due to intervention, assuming the pilot study baseline control rate of 0.53. These power calculations consider reductions of 0.25 and 0.20 transfers, which are plausible values within the confidence bounds in the ADRD-PC pilot study [Sites will enroll ot study . In TablAfter informed consent is obtained, data collection will be identical for both arms. Data will be obtained from caregiver enrollment interviews and 30- and 60-day interviews post-discharge and from electronic health record (EHR) reviews encompassing the 60-day period post-hospitalization. Based on the pilot RCT, we estimate 10% of persons with late-stage ADRD will die during follow-up; in these cases, caregiver interview data collection will proceed using a Bereavement Interview adaptation. Outcome measures will focus on 60-day interviews; 30-day interim interviews are necessary to support retention, ensure data capture for persons with ADRD who die, and for valid recall of hospital transfers (primary outcome) and secondary outcomes.Retention is supported by transitional care calls (on days 3 and 14 after discharge), appointments for follow-up interviews with recognizable CRC names and phone numbers, and a $25 gift card per interview.Data collection will be the responsibility of the site-based CRCs under the supervision of the site-based PI, with overall supervision from the PI and the project manager; the site-PIs will be responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported.All research data will be entered into REDCap, a 21 CFR Part 11-compliant data capture system provided by UNC . REDCap Participant confidentiality and privacy will strictly be held in trust by the participating investigators, their staff, the safety and oversight monitor(s), and the sponsor(s) and funding agency. This confidentiality is extended to the data being collected as part of this study. No personally identifiable information from the study will be released to any unauthorized third party without prior written approval of the sponsor/funding agency. The study participant’s contact information will be securely stored at each clinical site for internal use during the study. Data will be entered into a password-protected, secure database, and all paper documentation will be maintained in locked files. The Sheps Information Technology group, at UNC, enables standard operating procedures required to secure the network and databases, including operational and technical controls. All servers are located within a hardened data center.Patient and caregiver dyads will be the primary unity of analysis. Descriptive analyses of variables will examine distributions, influential data points, and missing data. All a priori analyses, primary and subgroup, will use intention-to-treat analysis. The effectiveness of randomization will be evaluated by comparing intervention and control participants on baseline measures because variables that are not equally distributed between arms could potentially bias results. We will include these variables in each initial model and use a change-in-effect method for determining whether they are confounders. Given our randomized design, we anticipate little confounding. A priori exploratory analyses will examine the effects by sex, race/ethnicity, and GDS stage.The control and intervention arms will be compared on hospital transfers (primary outcome) at 60 days post-discharge. This count outcome is defined as the total number of emergency room visits plus hospital admissions (including observation stays) per at-risk patient-days. Poisson regression with empirical “robust” standard errors allowing for overdispersion will be used to compare the transfer rates between groups. Length of follow-up will be used as the offset variable, which means that patients who have data only from the 30-day interview will be included. The primary analysis will be based on the model with the main effects for the treatment group, study site, GDS stage, and patient and caregiver sex as biological variables. Evaluation of the treatment effect will be based on a Wald test. The covariate-adjusted treatment effect will be quantified as an IRR with a 95% confidence interval. Considering that over 60% of patients in the pilot study did not have any hospital transfers, a sensitivity analysis will be conducted for the treatment effect on 60-day hospital transfers with a marginalized zero-inflated Poisson (MZIP) model , which mAn exploratory analysis will be conducted to examine the interactions of the treatment group with study site, sex, race/ethnicity, and GDS Stage on 60-day hospital transfers . An intet-test will be used to compare the mean difference between the study arms unless violation of assumptions warrants the Mann–Whitney test. A multiple linear regression model will be used with main effects for treatment group, study site, GDS stage, and patient and caregiver sex as a biological variable.Symptom treatment: This ordinal outcome is the summation of presence (= 1) or absence (= 0) of 10 domains of palliative care . It willSymptom control: The linear mixed models, with random intercepts for caregiver report of patients’ symptom distress (SM-EOLD)  and careUse of post-acute palliative care or hospice: This outcome will be defined as whether patients ever use hospice or outpatient palliative care during the time from discharge to 60 days follow-up. The proportions of those who do and do not use post-acute palliative care or hospice will be compared using Pearson’s chi-square test. Logistic regression will be used for multivariable modeling with the same main effects as in aim 2 . Final estimates will be reported as covariate-adjusted odds ratios.Transition to nursing home care: This outcome will be defined by whether patients transition to nursing home care during the time from discharge to 60 days follow-up. The proportions of those who do and do not transition to nursing home care will be compared using Pearson’s chi-square test. Logistic regression will be used for multivariable modeling with the same main effects as in aim 1. Final estimates will be reported as covariate-adjusted odds ratios.As described below, the control and intervention arms will be compared on patient secondary outcomes at 60 days post-discharge on the following outcomes:For the dichotomous outcome variables pertaining to communication about prognosis and goals of care and shared decision-making about hospitalization and shared decision-making about burdensome treatments, Pearson’s chi-square test will be used to test for differences in proportions between the study arms. We will use logistic regression for the multivariable modeling. Treatment effect estimates will be reported as adjusted odds ratios.t-test for the mean difference will be used since the outcome is continuous. Linear mixed models as described above will be used to test treatment effects for 30-day and 60-day outcomes jointly.To compare caregiver outcomes between intervention and control arms for caregiver distress (family distress in advanced dementia) , StudentThe control and intervention arms will be compared to caregiver secondary outcomes at 60 days post-discharge.No interim analyses are planned and this section is not applicable.An exploratory analysis will be conducted to examine the interactions of the treatment group with study site, sex, race/ethnicity, and GDS stage on 60-day hospital transfers and on secondary outcomes.Missing data on independent variables are expected to be minimal. Simple mean and mode imputation for those variables will be included in regression models if less than 5% of patients have missing data; otherwise, conditional  imputation will be used. Available case analysis will be conducted for 30-day outcomes. Missing 60-day dichotomous outcomes will be multiply-imputed if missingness exceeds 10%.The research team will be led by the PI and managed by the project manager reporting to the PI, who will provide administrative leadership and study coordination. This multi-site RCT will utilize a single IRB (UNC) and a unified protocol for all study sites. The UNC Cecil G. Sheps Health Services Research Center will be the administrative home for the UNC research investigators and staff. The project manager and data manager (UNC research staff) will facilitate data management, and data analysis will be led by the study biostatistician. The staff from the Palliative Care Research Cooperative Group’s Project Coordinating Center (University of Denver) will provide technical assistance to ensure good clinical practice, protocol version control, and central coordination of IRB tasks necessary for a large-scale multi-site clinical trial. Site-PIs in the research enrollment sites will oversee the study at UNC, IU, MGH/Harvard Medical School, UC, and Emory.The principal investigator (PI) will be responsible for ensuring the safety of participants daily. The Data and Safety Monitoring Board (DSMB), acting in an advisory capacity to the National Institute on Aging Director, will evaluate the progress of the study, review procedures for maintaining the confidentiality of data, the quality of data collection, management, and analyses.The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of study personnel during study visits and interviews. Study-tracked AEs will include major emotional distress for family caregivers and confidentiality risk events for the person with ADRD. Deaths, life-threatening health events, or acute illness episodes will be tracked for all participants; however, these are expected health outcomes for people with late-stage ADRD and will not be included in AE reporting. All AEs, not otherwise precluded per the protocol, will be captured on the appropriate case report form (CRF) and classified for severity and potential relationship to the study procedures. All harms and AEs occurring while on study will be documented appropriately regardless of relationship. Potential AEs and SAEs will be collected systematically for all study participants at each study visit, when research team members will inquire about the occurrence of AE/SAEs since the last visit. Potential AEs and SAEs will be collected non-systematically , when the occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of study personnel when a study participant presents for medical care or upon review by a study monitor. Any medical or psychiatric condition that is present at the time that the participant is enrolled will be considered as a baseline and not reported as an AE.Site-PIs will report any Unanticipated Problem Involving Risk to Subjects or Others (UPIRSO) or AEs to the PI and project manager in a timely manner. When a UPIRSO or AE is present, the PI and project manager will submit a report to the UNC IRB within 3 working days of receipt of this information. The reporting of any AE/SAE will be based on NIA and UNC IRB standards, on the severity of the AE (based on the Common Terminology Criteria for Adverse Events), its level of attribution to the intervention, and whether it is anticipated. All adverse events that are both serious (SAE) and unexpected would be reported to IRB, DSMB/SO, and NIA PO within 48 h of the study’s knowledge of SAE.Summary of SAEs will be reported to NIA, PO, and DSMB/PO quarterly, unless otherwise requested by the DSMB. Summary of all AEs regardless of classification will be presented for each DSMB meeting.All study protocols and amendments, informed consent forms, and other study materials will undergo review by the Institutional Review Board at UNC prior to initiating research and will be subject to annual and other required reviews. Any protocol changes will be reported to site-PIs. Changes will also be reported to study clinicians when these changes affect their roles.This study will be conducted in accordance with the National Institutes of Health (NIH) Public Access Policy. It requires scientists to submit final peer-reviewed journal manuscripts that arise from NIH funds to the digital archive PubMed Central upon acceptance for publication. Second, this study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. As such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed journals. Data from this study may be requested from other researchers 2 years after the completion of the primary endpoint by contacting the Palliative Care Research Collaborative Group . ConsideThis section is not applicable.The ADRD-PC study will be the first test of comprehensive dementia-specific palliative and transitional care. This study addresses the significant public health impact of late-stage ADRD and suffering due to symptom distress, burdensome treatments, and caregiver strain. While many caregivers prioritize comfort in late-stage ADRD, shared decision-making and access to specialty palliative care are rare. The ADRD-PC program leverages hospital palliative care teams to deliver comprehensive, dementia-specific palliative care plus transitional care. By including persons with GDS 5–7, ADRD-PC attends to the suffering of persons with ADRD and their caregivers along the illness trajectory rather than only at end-of-life.The study protocol is designed with consideration for potential problems and challenges. Palliative care cannot be ethically withheld from patients in the control group, and investigators anticipate the potential for contamination. Routine palliative care consultation will be permitted for controls, but contamination risk is decreased since in current care this is very uncommon. Even when control patients are seen by palliative care specialists, these clinicians will lack ADRD-PC dementia-specific training and tools. Any palliative care consultation for control dyads will be tracked. Furthermore, as indicated in the ADRD-PC pilot, most attending physicians determined the need for palliative care consultation in the first 1–2 days of admission. Thus, these patients are more likely to be excluded than to create bias to the null. Second, while not found in the single-site pilot, barriers to physician referral may exist at new sites. Site-PIs will function as opinion leaders and (supported by the PI) will provide in-person education to overcome any resistance. Third, sites may have difficulty implementing the EHR screening algorithm. The study team will work with them on alternative screening and case-finding strategies compatible with local practice norms. Fourth, sites may find that lengths of stay are too short for some persons with ADRD; if this occurs, we will consider alternative strategies to deliver some elements of the ADRD intervention via virtual visits.For persons with late-stage ADRD and their caregivers, there is an urgent need to improve outcomes of burdensome hospital transfers, symptom distress, shared decision-making, and caregiver distress. This study is responsive to the National Alzheimer’s Project Act, NIA priorities for geriatric palliative care, and quality care for ADRD. If efficacious, ADRD-PC has the potential for broad dissemination, as most US hospitals provide specialty palliative care.The study protocol (NCT03810534), version number 1, was registered on July 2, 2021. Key trial implementation milestones were achieved. First, in all sites, ADRD-PC tools were added to electronic health record systems (EPIC) between July 23 and November 15, 2021. Second, in all sites, ADRD-PC intervention training was completed between June 14 and July 9, 2021. Third, in four study sites, dyad enrollment was started between July 27 and November 16, 2021.Over the period from October to December 2021, the study team determined that COVID-related surges in hospital census were causing delays in participant enrollment. It was recognized that the original plan to achieve the sample within the study period was not feasible. Thus, in consultation with the NIA and the study DSMB, the study team developed a plan to add a fifth hospital to the multi-site RCT. The ADRD-PC protocol was revised, and the revised protocol (version 2.0) was approved by the UNC IRB on April 13, 2023, and updated on ClinicalTrials.gov . Subsequently, the ADRD-PC protocol was implemented in the fifth study site, Emory University (EU) Hospital in Atlanta, Georgia. In the EU Hospital, EPIC modifications and staff training were completed between March 7 and May 31, 2023, and enrollment of study participants was started on July 24, 2023. With the implementation of the ADRD-PC protocol in five hospitals, all participant enrollment is expected to be complete in May 2024.Finally, the ADRD-PC protocol was updated to incorporate a secondary study of a Spanish version of the ADRD-PC intervention. The Spanish language ADRD-PC protocol will permit enrollment of up to 50 additional dyads, generating data to be used in separate analysis to describe the feasibility and acceptability of the Spanish version of ADRD-PC. The revised protocol was approved by the UNC IRB on April 13, 2023, and updated on ClinicalTrials.gov .Additional file 1. Supplementary Material.Additional file 2.


Surgical resections remain the gold standard for early stages non-small-cell carcinoma (NSCLC) and may be considered for locally advanced tumors. Medical treatment has changed drastically in recent years, especially for advanced stages, for which the development of immunotherapy and molecular targeted therapy significantly increased survival and quality of life. The addition of radical surgical resection following immunotherapy or immuno-chemotherapy is feasible and safe with low surgical-related mortality and morbidity in selected patients with initially unresectable NSCLC.Many new treatment modalities for non-small-cell carcinoma (NSCLC) have been described in the last two decades. Surgical resections remain the gold standard for early stages and may be considered for locally advanced tumors. Medical treatment has changed drastically in recent years, especially for advanced stages, for which the development of immunotherapy and molecular targeted therapy significantly increased survival and quality of life. The addition of radical surgical resection following immunotherapy or immuno-chemotherapy is feasible and safe with low surgical-related mortality and morbidity in selected patients with initially unresectable NSCLC. However, data from multiple ongoing trials with overall survival as the primary endpoint should be awaited before this strategy is introduced into the standard of care. Lung cancer is the leading cause of cancer death worldwide. Many new treatment modalities for non-small-cell carcinoma (NSCLC) have been described in the last two decades, introducing thoracic surgery to a multimodality approach . SurgicaEarly-stage NSCLC is defined as localized cancer and refers to stages I, II, and IIIA as described by the 8th edition of TNM . LocallyHowever, locally advanced tumors also include those with a mediastinal lymph node involvement defining a very heterogeneous group of patients (stage IIIA-IIIB). For locally advanced tumors, surgery may be considered. However, optimal therapeutic management requires an interdisciplinary approach in order to evaluate the extension of the disease at the diagnosis, the patient’s comorbidities and the performance status before the operation, surgical operability, and a systemic induction treatment  when indicated for the disease stage, including its potentially toxic effects. In this case, to improve long-term outcomes, the treatment could include platinum-based chemotherapy and, in selected cases, a specific radiotherapy program to reduce tumor size and lymph node involvement before complete resection. Several studies compared survival and outcomes between definitive chemo-radiotherapy and surgery after induction treatment (chemotherapy or chemo-radiotherapy) .Chemotherapy drugs, especially platinum-based compounds, are associated with side effects . In thisRegarding tyrosine kinase inhibitors (TKI), the most commonly identified targets in the adenocarcinoma setting are activating gene K-RAS and EGFR , re-arraIn the last decade, different retrospective studies have shown significant outcome changes in previously unresectable diseases treated with tyrosine kinase inhibitors followed by lung resections for residual disease when feasible ,12. BaseErlotinib safety, tolerability, and pathological responses were evaluated in patients with EGFR-mutated NSCLC in a phase II study which showed encouraging results . A reasoRegarding the role of the immune checkpoint inhibitors, Durvalumab has been established in the PACIFIC trial as the standard of care for stage III unresectable NSCLC patients as consolidation therapy after concurrent chemoradiation . This roMany trials are studying the effects of tyrosine kinase inhibitors in this group of patients as consolidation therapy; for example, Osimertinib safety and efficacy are being assessed in a currently ongoing global phase 3 trial following concurrent or sequential chemoradiation in a patient with stage III (A/B/C) unresectable NSCLC and EGFR positive . ConversAdministering immune checkpoint inhibitors alone or in combination with chemotherapy and followed by surgical resections can benefit patients in terms of OS and DFS. Despite surgical resection being the standard of care for early-stage NSCLC, micrometastases, and isolated tumor cells are very challenging to detect by current technologies. Immune checkpoint inhibitors with or without chemotherapy combined with surgery can lower the probability of recurrence eradicating the micrometastases .Forde et al. in 2018, in one of the first single-arm clinical trials, showed the potential benefit of neoadjuvant Nivolumab followed by lung resection in a group of 21 patients with resectable NSCLC ranging from stage IB to IIIA. In his study, major pathological response and complete pathological response were achieved in nine and two patients, respectively . After tLCMC3 (Lung Cancer Mutation Consortium) trial, the most significant phase II trial reported to date, considered 181 patients with pathologically documented stage IB-IIIB resectable NSCLC, including T3N2 or T4 , who received before the surgery two cycles of Atezolizumab, and for those who showed clinical response, the treatment was continued for up to 1 year. In this group, 144 patients showed a major and complete pathological response in 20% and 7% of the cases, respectively. PD-L1 positivity and higher tumor mutation burden were correlated to a more significant pathological response .Other trials have been reported analyzing the role of neoadjuvant single-agent immunotherapy in resectable NSCLC. The role of Sintilimab was evaluated in 40 enrolled patients with stage IA-IIIB by Gao et al., 37 of whom underwent surgery. In this study, 40.5% achieved MPR and 16.2% pCR .Pembrolizumab efficacy and safety outcomes were evaluated in the NEOMUN trial. Fifteen patients with clinical-stage II-IIIA resectable NSCLC received two cycles of Pembrolizumab before surgery. Of the enrolled patients, 33% had relevant adverse effects. Two patients had MPR, and two other patients had pCR .Atezolizumab in the neoadjuvant setting was analyzed in the PRINCEPS trial in 30 patients with clinical IA (≥2 cm)-IIIA NSCLC. Among these, 29 had R0 resection. No pCR was reported, while 14% had MPR, and 41% had pathological response ≥ 50% .IONESCO is a phase II trial that analyzed the role of Durvalumab prior to surgical resection in 50 patients with stage IB (tumor ≥ 4 cm)-IIIA resectable NSCLC. Among these patients, 90% achieved R0, with an MPR of 18.6% and pCR of 7%. The enrolment in this study was stopped due to 9% of death at 90 days, attributed by the authors not to Durvalumab toxicities but to pre-existing comorbidities .Tong et al. published in February 2022 a study that examines the safety and efficacy of neoadjuvant Pembrolizumab in stage IB to IIIA NSCLC. Thirty-five patients were enrolled, thirty received two cycles of Pembrolizumab, and twenty-five underwent surgery  followed by a complete resection in 88% of the cases. In this case series, neoadjuvant Immune Checkpoint Inhibitors (ICIs) seem safe and tolerated, and no association with increased toxicity, delays before surgery, or additional surgical morbidity was reported .The role of radiotherapy in combination with immunotherapy as an immunomodulator has been assessed by Altorki et al. His group examined the combination of neoadjuvant Durvalumab with stereotactic body radiotherapy in patients with early-stage lung cancer (I-IIIA). This randomized, single-center phase II trial evaluates the immunomodulatory activity of radiotherapy in patients with early-stage NSCLC enhancing the antitumor immune response associated with the anti-PD-L1 antibody Durvalumab. In this trial, stereotactic body radiotherapy might be a potent immunomodulator in advanced NSCLC, is well tolerated, and is associated with a higher major pathological response rate than the Durvalumab monotherapy group  Table 1Table 1.Several studies have demonstrated the superiority in oncological outcomes of immunochemotherapy compared to chemotherapy alone in the neoadjuvant setting from early stage to locally advanced NSCLC patients .Shu et al. published a phase II multicenter study of Atezolizumab and chemotherapy (carboplatin plus nab-paclitaxel) for up to four cycles in 30 patients affected by resectable NSCLC stage IB-IIIA and smoking history. Twenty-three patients had stage IIIA disease, and 87% underwent complete tumor resection .In the NADIM II trial, which enrolled 86 patients with stage IIIA or stage IIIB disease and no known EGFR or ALK alterations, the pathologic complete response rate was 36.8% in 57 patients who received Nivolumab plus Paclitaxel and Carboplatin against 6.9% rate observed among the 29 patients treated with neoadjuvant chemotherapy alone. Provencio et al. also reported a higher major pathologic response in the first group, 52.6% vs. 13.8%, respectively. This trial confirms the superiority of the neoadjuvant Nivolumab plus chemotherapy combinations in patients with resectable stage IIIA-B NSCLC. These preliminary results were presented at the 2022 American Society of Clinical Oncology (ASCO) annual meeting in Chicago and the International Association for the Study of Lung Cancer (IASLC) 2022 World Conference on Lung Cancer (WCLC) in Vienna. The immunotherapy combination maintained a tolerable safety profile and a moderate increase in grade 3–4 toxicity .Another phase III trial named CheckMate 816 compares three cycles of neoadjuvant Nivolumab plus platinum-doublet chemotherapy with the control arm alone. According to the seventh edition staging, this study enrolled 358 patients with stage IB-II-IIIA NSCLC. The pathologic complete response and major pathologic response were higher in patients treated with immunochemotherapy than those treated with chemotherapy, 24% vs. 2% and 37% vs. 9%, respectively. Spicer presented the surgical outcomes of this study at the ASCO Annual Meeting in 2021. These results revealed that a higher number of patients underwent surgery with no interference in feasibility or timing in the study group compared to the standard group (83% vs. 75%). More patients underwent lobectomies, and fewer underwent pneumonectomies compared to the standard group who received chemotherapy alone (77% vs. 61% and 17% vs. 25%).Moreover, no increase in toxicity of postoperative complications was reported in the study group with the addition of ICIs . FollowiIn 2022, the Checkmate 816 results were published. More prolonged event-free survival (HR 0.63), a higher percentage of pCR (24% vs. 2.2%), better OS, time to distant metastases, MPR, and radiographic downstaging were reported for Nivolumab plus chemotherapy compared to chemotherapy alone as neoadjuvant treatment in resectable NSCLC. In addition, no increase in adverse effects or decrease in the feasibility of surgery was reported in the study group .KEYNOTE 671 evaluates the safety and efficacy of Pembrolizumab in combination with platinum doublet neoadjuvant chemotherapy before surgery, followed by Pembrolizumab alone after surgery in resectable stage II, IIIA, and resectable IIIB (T3-4N2) NSCLC .AEGEAN assesses the activity of Durvalumab and chemotherapy in stage II-III NSCLC patients, administered before surgery, compared with placebo and chemotherapy administered before surgery in terms of complete pathological response, with encouraging preliminary results. A statistically significant improvement in major pathologic response was observed .CheckMate 77T trial evaluates neoadjuvant Nivolumab in combination with chemotherapy followed by adjuvant Nivolumab in resectable stage IIA–IIIB (T3N2 only) NSCLC patients. The primary endpoint of the study is EFS .IMPOWER 030 study evaluates the safety and efficacy of Atezolizumab in combination with platinum-based chemotherapy as a neoadjuvant treatment in resectable stage II-III NSCLC patients .Several other phases III neoadjuvant chemotherapy plus immune checkpoint inhibitors studies are ongoing, such as:Most studies demonstrate the efficacy and tolerability of immune checkpoint inhibitors in the unresectable NSCLC in the adjuvant setting.Chemotherapy has been the standard of care for patients with NSCLC as adjuvant therapy, improving the 5-year survival rates by only 4–5%.Adjuvant therapy plays an essential role in preventing recurrence and eliminating micrometastases. To date, new targeted therapies have been described that showed better DFS than chemotherapy, such as Osimertinib , GefitinWu et al. reported in ADAURA that 90% of patients with stage II to IIIA were alive at 24 months in the Osimertinib group and only 44% in the placebo group.In recent years, ICIs have become more and more utilized for unresectable locally advanced or metastatic stages with very promising results, as described in the following paragraphs. Based on these results, several new trials are studying the efficacy of ICIs also in early-stage NSCLC patients.IMpower 010: open-label phase III study with a sample size of 1280 patients from 22 countries. This trial includes EGFR mutations and ALK rearrangements. A total of 1005 patients were randomized to receive adjuvant Atezolizumab (507) or best supportive care (498). In patients with stage II-IIIA NSCLC and an expression of PD-L1 ≥ 1%, the patients who had disease progression were 35% of patients receiving Atezolizumab and 46% of patients receiving best supportive care, reducing the risk of recurrence by 34%  . Due to KEYNOTE-091: phase III trial with a sample size of 1177 patients with stage IB-IIIA. In this study, patients after adjuvant chemotherapy are randomized to receive adjuvant Pembrolizumab or placebo for one year . PrelimiBR31/IFCT1401: phase III trial with a sample size of 1415 patients with a stage IB-IIIA NSCLC. After adjuvant chemotherapy, patients are randomized to receive Durvalumab or a placebo for one year. The outcome studied is DFS in patients with PD-L1 ≥ 25% without EGFR mutations or ALK rearrangements .ANVIL, ALCHEMIST Chemo-IO, MERMAID-1, MERMAID-2, NADIM-ADJUVANT, and LungMate-008 are ongoing trials studying efficacy, the DFS and the OS of adjuvant ICIs  in patients with resectable NSCLC  :IMpower As described in the NCCN guidelines, the recommended duration of Atezolizumab as adjuvant therapy is one year . In the For unresectable NSCLC, several therapeutic strategies have been proposed in the last decade. these treatments could range from local therapies (such as radiotherapy) to systemic therapies , which may be used alone or in association with each other.One of the most representative studies regarding the association between chemotherapy and radiotherapy was published in 2014. In this view, sequential and concurrent chemotherapy were compared in a group of stage III unresectable NSCLC patients. For sequential therapy, the median Overall survival (OS) and the 5-year survivals were 17.4 months and 17%, respectively, against a median OS of 18.6 months and a 5-year survival rate of 19% for the concurrent chemo-radiotherapy group .Bradley and colleagues described in 2015, in a randomized phase 3 study, concurrent chemotherapy associated with standard-dose versus high-dose radiotherapy in patients with locally advanced stage III unresectable NSCLC. In this study, unfortunately, most of the initially unresectable locally advanced NSCLC patients experienced disease progression, despite definitive treatment .Considering these findings, several efforts have been made to increase the OS and DFS in unresectable NSCLC patients, and in this view, different authors focused mainly on immunotherapy. In 2017, in a large study published in the New England Journal of Medicine (NEJM), Antonia et al. demonstrated a significant improvement in OS and time to distant metastatic disease using chemoradiation followed by 12 months consolidation immunotherapy with Durvalumab in unresectable stage III NSCLC patients, becoming the new standard of care . This raAll the PD-L1 subgroup patients showed increased OS and DFS when treated with Durvalumab against a placebo. The only doubt about the immunotherapy benefit regards the negative PD-L1 patients. In this latter subgroup, Durvalumab positively impacted PFS but not OS.These study results have been taken into account by several associations. The European Medicines Agency (EMA) has concluded that patients with stage III NSCLC with PD-L1 < 1% should not receive treatment with Durvalumab . This co50 early deaths before study enrolment were not counted in the Germany and UK sites.RECIST criteria  for tumor assessment has been used heterogeneously across different countries.In the real world, assessment for disease progression may not occur as frequently and systematically as in other clinical trials. Moreover, the COVID-19 pandemic has also resulted in fewer hospital visits and inconsistent follow-up.In view of this, the PACIFIC-R, a real-world international and observational study, was presented at the European Society of Medical Oncology (ESMO) congress in 2021 and included 1399 patients from 11 participating countries: France (342), Spain (244), Australia (165), Netherlands (155), Belgium (188), Italy (116), Israel (92), Germany (62), UK (54), Norway (36), and Switzerland (15). This study focused on treatment duration and analysis of PFS in unresectable stage III NSCLC patients treated with Durvalumab after chemo-radiotherapy regardless of tumor PD-L1 expression. The primary endpoints assessed were PFS and OS. An essential inclusion criterion was the non-evidence of progression following platinum-based chemotherapy concurrent or sequential to radiotherapy within the previous 12 weeks. Patients were treated with Durvalumab (10 mg/kg IV q2W), and retrospective data were collected at different time points. The median time to Durvalumab initiation from the end of RT was 56 days. The overall median Durvalumab treatment duration was 335 days. Patients received a median of twenty-two Durvalumab infusions. 76.8% of patients received concurrent chemo-radiotherapy, and 14.6% received sequential chemo-radiotherapy. There were no significant differences in baseline characteristics, except for patients older than 70 years old and the longest dimension of the primary tumor. The median PFS in PACIFIC-R was higher than the median PFS reported for the Durvalumab arm of the PACIFIC trial. In this “real-world study,” the median follow-up duration was 23 months, but it is likely overestimated due to several factors:The median PFS in patients PD-L1 > 1% was 22.4% instead of 16.3% in PD-L1 negative. The PFS was 23.7% in stage IIIA and 19.2 months in stage IIIB/C. Once again, the PFS was 25.3 in non-squamous lung cancer patients and 14.7 months in squamous cancer patients. The PFS was 23.7 months in concurrent chemo-radiotherapy vs. 19.4 months in the sequential chemo-radiotherapy subgroup of patients.The most common adverse effect of Durvalumab was pneumonitis/interstitial lung disease (LID), leading to a permanent discontinuation in 9.5% or a temporary interruption in 5.2% of the cases. The median time to onset pneumonitis/LID from Durvalumab initiation was 2.5 months, and corticosteroid administration was required in 71.3% of the cases .n = 114) had a PFS of 13.1 months; conversely, patients classified as ECOG PS 2 (n = 3) had a PFS of only 3.7 months. Considering the low sample size of the latter group, these results could not be statistically significant [PACIFIC-6 is an ongoing phase II open-label and multicenter study where patients with unresectable stage III NSCLC, who have not progressed following platinum-based sequential chemoradiation therapy, receive Durvalumab 1500 mg IV q4w up to 24 months or until disease progression, with safety and tolerability as primary endpoints. Considering the adverse effects correlated to therapy, 70% were of any grade against 4% of grades 3 and 4. Among the 117 patients, 25 discontinued Durvalumab for side effects, 9 of which were mainly for pneumonitis. As a secondary outcome, PFS was considered in this study. Until now, preliminary results were PFS related to ECOG performance status (PS). Patients classified as ECOG PS 0–1  in patients with locally advanced, unresectable NSCLC (stage III) compared to placebo plus CRT followed by placebo. The estimated study completion date is November 2023 .In synthesis, these first different trials showed an improved OS and PFS in unresectable stage III NSCLC patients treated with Durvalumab after CRT, especially if the tumor is adenocarcinoma at earlier stages, if the PD-L1 is positive and if the CRT is concurrent over sequential chemo-radiotherapy. The rationale of the CRT followed by Durvalumab is that chemoradiation induces tumor antigen release and adaptive immune response, and therefore PD-L1 overexpression leads to immune cell evasion. In this scenario, Durvalumab reverses immune suppression and leads to a systemic antitumor response. Nevertheless, results shared by the PACIFIC trial have been considered improvable, as only approximately 50% of the patients are alive after four years of Durvalumab initiation. In this view, Durvalumab and several other immune checkpoint inhibitors alone or combined with systemic therapy, chemotherapy, and radiotherapy have been studied to improve OS and PFS in NSCLC and SCLC patients.COAST  is a global, open-label, randomized, Phase II study of Durvalumab alone or combined with the anti-CD73 mAb Oleclumab or anti-NKG2A mAb Monalizumab as consolidation therapy in patients who have not progressed after concurrent chemo-radiotherapy. This is the first study showing improved outcomes with novel immune-oncology combinations in the PACIFIC setting.The rationale for using Oleclumab and Monalizumab is that radiotherapy induces CD73 and HLA-E (NKG2A ligand) expression, which inhibits the antitumor immune response. Oleclumab inhibits CD73 to reduce extracellular adenosine production, thereby promoting antitumor immunity, and it has been shown to have a durable response and manageable safety when combined with Durvalumab in a phase I study. Monalizumab reduces the inhibition of NK and CD8+ T cells by blocking NKG2A.Between January 2019 and July 2020, 189 patients were randomized, of whom 66 received Durvalumab, 59 received Durvalumab plus Oleclumab, and 61 received Durvalumab plus Monalizumab. Study results were published in the Journal Clinical of Oncology in 2022, indicating that the combination of Oleclumab or Monalizumab with Durvalumab provides an additional clinical benefit over Durvalumab alone in patients with unresectable, stage III NSCLC without disease progression following cCRT. After a median follow-up of 11.5 months , the objective response rate (ORR) was higher for both the combinations  compared to Durvalumab alone (30%).Both combinations also significantly improved PFS versus Durvalumab alone. PFS benefit with both combinations was observed across various subgroups, including those based on histology, ECOG PS, prior platinum-based CT, and PD-L1 status. Median PFS was 6.3  with Durvalumab, not reached  with Durvalumab plus Oleclumab and 15.1 months  with Durvalumab plus Monalizumab. Safety profiles were consistent across arms, with no significant safety signals identified in either combination arm. The incidence of adverse effects for Durvalumab, including pneumonitis, were similar across arms .These findings have led to the phase III PACIFIC-9 study, which is a phase III, double-blind, multicenter international study of Durvalumab plus Oleclumab and Durvalumab plus Monalizumab for the treatment of patients who have not progressed following concurrent chemoradiation treatment for locally advanced, stage III, unresectable NSCLC. This trial started in February 2022 and assessed PFS and OS between these drugs and their safety and tolerability .Another successful combination between immune checkpoint agents has been reported by Cho et al. in the CITYSCAPE clinical trial, which analyzed the effects of Tiragolumab, an anti-T-cell immunoreceptor with Ig and ITIM domains (anti-TIGIT), in combination with Atezolizumab (anti-PD-L1) in chemotherapy-naïve, PD-L1 positive, locally advanced, and metastatic NSCLC. CITYSCAPE is a phase II, randomized, double-blind, placebo-controlled trial, which showed an improved ORR and PFS in the anti-TIGIT with anti-PD-L1 therapy combination with more significant benefit observed in the PD-L1 tumor proportion score (TPS) ≥ 50%. Tiragolumab and Atezolizumab were well-tolerated, with a safety profile similar to placebo plus Atezolizumab . Based oPembrolizumab, Nivolumab, Ipilimumab, and Durvalumab are being studied alone or in combination with other systemic therapies or radiotherapy in several other phases II and phase III ongoing trials, some of these with already preliminary results , to evaluate the safety, efficacy, PFS, and OS in unresectable stage III NSCLC patients ,73,74,75Additional immunomodulation through combination therapy is being explored to improve clinical outcomes in this patient population.Starting from 2018, retrospective data have shown limited activity of ICI monotherapy in patients with advanced NSCLC with specific driver genomic alterations (dGA). Mazieres et al. reported an overall survival of 13.3 months and a PFS of 2.8 months in the whole cohort of 551 patients. Outcomes for patients with dGA  were inferior, so ICI should be considered after exhaustion of other systemic therapies such as targeted or chemotherapies or combined with chemotherapy. With comparable results in 2020, Guisier et al. studied the efficacy of ICI against patients with dGA-NSCLC that seemed close to that observed in unselected patients with NSCLC. ,77. MoreRiudavets M. et al. presented at the ESMO Congress 2021 preliminary outcome results of Durvalumab as consolidation therapy in patients with stage III unresectable NSCLC with driver genomic alterations, which was then published in January 2022 in the European Journal of Cancer. This multicenter retrospective study has 25 participating centers from Europe, the United States, and Argentina. Out of 323 patients included from April 2015 to October 2020, 43 had at least one dGA . Among these, 13% had negative PD-L1 status. In the overall population, the median follow-up was 18.5 months  with a median PFS of 17.5 months  and median OS of 47.0 months . Considering the PD-L1 status, no differences in median PFS between the PD-L1 positive and PD-L1 negative population were reported. Moreover, no differences in median PFS between dGA (14.9 months) and non-dGA groups (18 months) were reported .Considering Durvalumab outcomes by molecular subgroups, this study observed differences for Durvalumab as PFS among the different molecular subgroups in stage III unresectable NSCLC; patients with NSCLC with KRAS mutation had better ICI outcomes, in contrast to patients with other driver molecular alterations, such as EGFR mutations, BRAF mutations or ALK rearrangements.Based on these results, this study showed the limited activity of Durvalumab in stage III unresectable NSCLC patients with EGFR mutation, BRAF mutation, and ALK rearrangement but not for KRAS mutation. In the latter case, patients with this rearrangement should still receive immunotherapy consolidation in multidisciplinary evaluation .These studies show no benefit for immunotherapy  in dGA-NSCLC patients, except for NSCLC patients harboring KRAS mutation .Several studies and trials reported the outcomes of anti-PD-1/PD-L1 monotherapy alone or in combination with platinum doublet chemotherapy or cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) blocking antibody against standard platinum doublet chemotherapy in advanced NSCLC patients .More specifically, in the last decade, different clinical trials evaluated the use of Pembrolizumab as anti-PD-L1 monotherapy compared to the standard-of-care chemotherapy analyzing its OS, PFS, ORR, tolerability, and safety.The approval of Nivolumab for advanced NSCLC by the FDA was based on two phase III clinical trials, Checkmate 017 and Checkmate 057 ,80. The Keynote-001, Keynote-024, and Keynote-042 demonstrated exciting results favoring Pembrolizumab over chemotherapy regardless of PD-L1 expression ,82,83.However, in 2011, the first CTLA-4 inhibitor to receive FDA approval was Ipilimumab for patients with metastatic melanoma . AnotherGovindan et al. reported the results of a phase III trial on Ipilimumab combined with Paclitaxel and Carboplatin in advanced squamous NSCLC. In this study, no significant OS benefit was demonstrated in the chemoimmunotherapy group compared to chemotherapy alone, and more toxicity was related to treatment with Ipilimumab, resulting in many cases of discontinuation and reduced potential benefit .In this view, advanced NSCLC patients are being studied in several ongoing trials, which now focus on treatment based on CTLA-4 inhibitors in combination with other immune checkpoint inhibitors with or without the addition of chemotherapy.In contrast, the combination of Tremelimumab and Durvalumab compared to chemotherapy was evaluated in the phase III MYSTIC and NEPTUNE trials. Both trials showed no benefit in OS or PFS with the combination of these two therapies.The only difference in results was the improvements in Rizvi et al. study of OS, PFS, and ORR for this combination versus chemotherapy in specific patients with blood-based TMB measurement (bTMB) > 20 mut/Mb; these results could not be replicated in bTMB < 20 mut/Mb ,86.Solange Peters presented POSEIDON clinical trial preliminary results at IASLC’s 2022 World Conference on Lung Cancer. Patients with metastatic NSCLC who received combined therapy of Tremelimumab, Durvalumab, and chemotherapy experienced higher 24-month OS compared to patients who received chemotherapy alone, regardless of STK11, KEAP1, or KRAS mutational status. This trial supports combining therapy as a potential first-line treatment option for these patients .Another combination of therapies is Ipilimumab plus Pembrolizumab, which showed no benefit in advanced NSCLC. KEYNOTE-021 is a phase I/II trial that studied this combination at different dosing regimens. The primary endpoint of this trial was not met by the objective response rate of 30%, and no correlation was found with the PD-L1 tumor proportion score. The authors concluded that the combination had potential antitumor activity but with associated toxicity .KEYNOTE 598 trial compared Pembrolizumab and Ipilimumab to Pembrolizumab alone in PD-L1 > 50% advanced NSCLC patients. PFS and OS were the primary endpoints in this case, but the trial was stopped due to no correlation with the better benefit of combination therapy over Pembrolizumab alone .EMPOWER-lung 4 study is a phase II trial analyzing the efficacy of anti-PD-1 Cemiplimab alone at different doses or in combination with Ipilimumab. If treated with combination therapy, the primary endpoint ORR rate was 45.5% in PD-L1 1–50% and 36% in the PD-L1 negative population .The Checkmate 012 study evaluated the different doses of Nivolumab and Ipilimumab in patients with recurrent stage IIIB or chemotherapy-naïve stage IV NSCLC . SimilarIn 2020, the FDA approved this therapeutic strategy in PD-L1-positive advanced NSCLC as a first-line treatment . FriedlaThe same drugs were analyzed in a different regimen in Checkmate 9LA, a phase III trial that showed that the combination of Nivolumab and Ipilimumab with chemotherapy is associated with a significant improvement in overall survival in metastatic NSCLC compared to doublet chemotherapy alone. The benefit was seen in this study group regardless of the PD-L1 positivity and the histology (squamous and non-squamous) . This quThe combination of Nivolumab and Ipilimumab with or without chemotherapy is approved as the first-line strategy for PD-L1-positive NSCLC. However, it is still unclear the role of this therapy in metastatic NSCLC, especially considering the cost-effectiveness as described by Courtney et al. The authors concluded that to be cost-effective, immunotherapy should not exceed four months .Despite the OS benefit of the combination immunotherapy demonstrated in the Checkmate 227 trial, this strategy is associated with an increased cost. Furthermore, treatment-related adverse events are more associated with adding Ipilimumab to chemotherapy or Nivolumab and chemotherapy ,93.Conversely, the Checkmate 9LA trial showed treatment-related adverse events in 47% of the cases treated with the quadruplet regimen compared to a 38% rate in the chemotherapy alone therapy . ComparaAnother treatment for metastatic NSCLC patients that have been studied is the combination of Ipilimumab with radiation. NCT02239900 is a phase I/II trial studying Ipilimumab and hypofractionated stereotactic radiation therapy (SBRT) as treatment in advanced NSCLC patients.This trial evaluates the maximum dose tolerated by Ipilimumab associated with SBRT .NCT03223155 evaluates the safety of concurrent or sequential Ipilimumab instead of Nivolumab and SBRT in patients with Stage IV NSCLC .Mazieres et al. reported a large retrospective study that demonstrated the poor clinical efficacy of immunotherapies in metastatic NSCLC patients with driver mutations. Especially in patients with EGFR or ALK mutations, the objective response rate was 12% and 0%, respectively, and the PFS were 2.1 and 2.5 months. For this reason, this therapy class has been abandoned in this patient population .CTLA-4 inhibitors monotherapy or in combination with checkpoint inhibitors in metastatic NSCLC patients with targetable mutations have been evaluated only in very few studies and have been associated with adverse effects leading to early closure for safety .One of these studies evaluated the combination of Ipilimumab with Erlotinib or Crizotinib as a first-line treatment strategy. Despite several adverse effects related to the treatment, such as colitis and leading to the early closure of this study, the long-term follow-up showed promising results with a median PFS of 17.9 and 21.4 months and a median OS of 42 and 47 months for 11 patients with EGFR and three patients with ALK mutation on trial, respectively. However, the reasons for these survival results are still not completely understood .Considering these results, another phase I clinical trial evaluates the safety and efficacy of the combination of Osimertinib with Ipilimumab (NCT041141644).Further clinical trials are studying the CTLA-4 inhibitor combinations in advanced EGFR/ALK mutation NSCLC patients with failed targeted therapy.CheckMate 722 evaluates Nivolumab in addition to chemotherapy to Ipilimumab or chemotherapy alone in NSCLC patients with EGFR mutations who have failed first- or second-line EGFR TKI therapy (NCT02864251) . The stuIn addition, another single-institution phase II study (NCT03256136) is evaluating Nivolumab plus chemotherapy, or Nivolumab in combination with Ipilimumab in EGFR or ALK mutated NSCLC patients who failed TKI therapy. Furthermore, NCT03091491 is a phase II study in Asia evaluating Nivolumab versus the combination of Nivolumab and Ipilimumab in a patient with EGFR mutation NSCLC who has failed first-line TKI therapy ,107. TheInduction immunotherapy with or without chemotherapy can be considered for unresectable locally advanced NSCLC, and after the downstaging, the possibility of surgery could be re-evaluated in a multidisciplinary setting with high rates of R0 resection. Furthermore, current data showed that lung resection for early-stage NSCLC followed by immunotherapy is safe and feasible.Future research can help identify an objective biomarker to reliably predict the benefit of immunotherapy, the number of cycles and duration of immunotherapy in the preoperative or postoperative setting, and the optimal combination with other systemic therapies.