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Nivolumab has shown improved survival in the treatment of advanced non-small-cell lung cancer (NSCLC) previously treated with chemotherapy. We assessed the safety and activity of combination nivolumab plus ipilimumab as first-line therapy for NSCLC. The open-label, phase 1, multicohort study (CheckMate 012) cohorts reported here were enrolled at eight US academic centres. Eligible patients were aged 18 years or older with histologically or cytologically confirmed recurrent stage IIIb or stage IV, chemotherapy-naive NSCLC. Patients were randomly assigned (1:1:1) by an interactive voice response system to receive nivolumab 1 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks, nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 12 weeks, or nivolumab 3 mg/kg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks until disease progression, unacceptable toxicities, or withdrawal of consent. Data from the latter two cohorts, which were considered potentially suitable for further clinical development, are presented in this report; data from the other cohort (as well as several earlier cohorts) are described in the appendix. The primary outcome was safety and tolerability, assessed in all treated patients. This ongoing study is registered with ClinicalTrials.gov, number NCT01454102. Between May 15, 2014, and March 25, 2015, 78 patients were randomly assigned to receive nivolumab every 2 weeks plus ipilimumab every 12 weeks (n=38) or nivolumab every 2 weeks plus ipilimumab every 6 weeks (n=40). One patient in the ipilimumab every-6-weeks cohort was excluded before treatment; therefore 77 patients actually received treatment (38 in the ipilimumab every-12-weeks cohort; 39 in the ipilimumab every-6-weeks cohort). At data cut-off on Jan 7, 2016, 29 (76%) patients in the ipilimumab every-12-weeks cohort and 32 (82%) in the ipilimumab every-6-weeks cohort had discontinued treatment. Grade 3–4 treatment-related adverse events occurred in 14 (37%) patients in the ipilimumab every-12-weeks cohort and 13 (33%) patients in the every-6-weeks cohort; the most commonly reported grade 3 or 4 treatment-related adverse events were increased lipase (three [8%] and no patients), pneumonitis (two [5%] and one [3%] patients), adrenal insufficiency (one [3%] and two [5%] patients), and colitis (one [3%] and two [5%] patients). Treatment-related serious adverse events were reported in 12 (32%) patients in the ipilimumab every-12-weeks cohort and 11 (28%) patients in the every-6-weeks cohort. Treatment-related adverse events (any grade) prompted treatment discontinuation in four (11%) patients in the every-12-weeks cohort and five (13%) patients in the every-6-weeks cohort. No treatment-related deaths occurred. Confirmed objective responses were achieved in 18 (47% [95% CI 31–64]) patients in the ipilimumab every-12-weeks cohort and 15 (38% [95% CI 23–55]) patients in the ipilimumab every-6-weeks cohort; median duration of response was not reached in either cohort, with median follow-up times of 12·8 months (IQR 9·3–15·5) in the ipilimumab every-12-weeks cohort and 11·8 months (6·7–15·9) in the ipilimumab every-6-weeks cohort. In patients with PD-L1 of 1% or greater, confirmed objective responses were achieved in 12 (57%) of 21 patients in the ipilimumab every-12-weeks cohort and 13 (57%) of 23 patients in the ipilimumab every-6-weeks cohort. In NSCLC, first-line nivolumab plus ipilimumab had a tolerable safety profile and showed encouraging clinical activity characterised by a high response rate and durable response. To our knowledge, the results of this study are the first suggestion of improved benefit compared with anti-PD-1 monotherapy in patients with NSCLC, supporting further assessment of this combination in a phase 3 study. Bristol-Myers Squibb.

BackgroundCheckMate 817, a phase 3B study, evaluated flat-dose nivolumab plus weight-based ipilimumab in patients with metastatic non-small cell lung cancer (NSCLC). Here, in this research, we report on first-line treatment in patients with Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0–1 (cohort A) and special populations (cohort A1: ECOG PS 2; or ECOG PS 0–1 with untreated brain metastases, renal impairment, hepatic impairment, or controlled HIV infection).MethodsCohorts A and A1 received nivolumab 240 mg every 2 weeks plus ipilimumab 1 mg/kg every 6 weeks. The primary endpoint was the incidence of grade 3–4 and grade 5 immune-mediated adverse events (IMAEs; adverse events (AEs) deemed potentially immune-related, occurring <100 days of last dose, and treated with immune-modulating medication (except endocrine events)) and treatment-related select AEs (treatment-related AEs with potential immunological etiology requiring frequent monitoring/intervention, reported between first dose and 30 days after the last dose) in cohort A; efficacy endpoints were secondary/exploratory. In cohort A1, safety/efficacy assessment was exploratory.ResultsThe most common grade 3–4 IMAEs were pneumonitis (5.1%), diarrhea/colitis (4.9%), and hepatitis (4.6%) in cohort A (N=391) and diarrhea/colitis (3.5%), hepatitis (3.5%), and rash (3.0%) in cohort A1 (N=198). The most common grade 3–4 treatment-related select AEs were hepatic (5.9%), gastrointestinal (4.9%), and pulmonary (4.6%) events in cohort A and gastrointestinal (4.0%), skin (3.5%), and endocrine (3.0%) events in cohort A1. No grade 5 IMAEs or treatment-related select AEs occurred. Treatment-related deaths occurred in 4 (1.0%) and 3 (1.5%) patients in cohorts A and A1, respectively. Three-year overall survival (OS) rates were 33.7% and 20.5%, respectively.ConclusionsFlat-dose nivolumab plus weight-based ipilimumab was associated with manageable safety and durable efficacy in cohort A, consistent with data from phase 3 metastatic NSCLC studies. Special populations of cohort A1 including patients with ECOG PS 2 or ECOG PS 0–1 with untreated brain metastases had manageable treatment-related toxicity and clinically meaningful 3-year OS rate.Trial registration numberNCT02869789.

Background Patients with small‐cell lung cancer (SCLC) primarily present with extensive stage (ES) disease and poor 5‐year survival. There are few treatment options and limited data on outcomes in third‐line (3L) ES SCLC to quantify unmet medical needs. This chart review evaluated real‐world (RW) clinical outcomes and treatment patterns in these patients. Methods This retrospective study using electronic medical records included adult patients with ES SCLC (≥ 2 claims for metastasized lung cancer) who received ≥ 3 lines of therapy (LOT) at Cancer Treatment Centers of America (now City of Hope). Patients with other/multiple primary malignancies, non‐SCLC histology, or treated through a clinical trial were excluded. Clinical outcomes included RW physician‐reported response rates, duration of response (DOR), duration of clinical benefit (DoCB), overall survival (OS), and progression‐free survival (PFS), stratified by platinum sensitivity and Eastern Cooperative Oncology Group performance status (ECOG‐PS). Time‐to‐event outcomes were estimated via Kaplan–Meier. Treatment patterns were assessed, including the sequence of regimens by LOT and first‐line (1L) platinum sensitivity status. Results Among 113 eligible patients (median age 58 years), 54% were female, and 46% had a chemotherapy‐free interval after 1L of < 90 days. Tumor shrinkage, complete response, and stable disease were reported in 19%, 1%, and 13% of patients at 3L, respectively. The median DOR, DoCB, OS, and PFS were 2.8, 2.5, 5.8, and 2.4 months in 3L, respectively. Platinum‐resistant versus sensitive patients in 1L had shorter time‐to‐event outcomes. Clinical outcomes were similar regardless of ECOG‐PS status. Platinum‐based chemotherapy rates decreased from 94% and 93% in 1L to 17% and 16% in 3L in platinum‐sensitive and resistant patients, respectively. Conclusion These RW findings validate 3L results from clinical trials, demonstrating the limited clinical benefits with current therapies in 3L ES SCLC, and highlighting the urgent need for novel therapies that improve outcomes in this difficult‐to‐treat patient population.

Background The availability of new immuno-oncology therapeutics markedly impacts oncology clinicians’ treatment decision-making. To effectively support healthcare professionals (HCPs) in their practice, it is important to better understand the challenges and barriers that can accompany the introduction of these agents. This study aimed to establish the types and causes of clinical challenges posed by the introduction of new immuno-oncology agents. Methods The mixed-methods design included qualitative in-depth interviews and group discussions with HCPs, in which participants discussed clinical challenges and potential underlying reasons for these challenges. Qualitative findings informed a quantitative survey. This survey investigated the extent and distribution of challenges using HCPs’ self-rating of knowledge, skill, confidence, and exposure to system-level effects. These two phases were conducted sequentially with distinctly stratified samples of oncologists, nurse practitioners (NPs), physician assistants (PAs), pathologists, clinical pharmacists, interventional radiologists, rheumatologists, pulmonologists, and emergency department physicians. Participants were from the United States and had various levels of clinical experience and represented both academic and community-based settings. Results The final sample included 107 HCPs in the qualitative phase and 554 in the quantitative phase. Analyses revealed clinical challenges related to the use of pharmacodiagnostics. For example, 47% of pathologists and 42% of oncologists reported skill gaps in identifying the appropriate marker and 46% of oncologists, 61% of PAs, 66% of NPs, 74% of pulmonologists and 81% of clinical pharmacists reported skill gaps in selecting treatment based on test results. Challenges also emerged regarding the integration of immuno-oncology agents, as oncologists, rheumatologists, pulmonologists, clinical pharmacists, PAs, and NPs reported knowledge gaps (74-81%) of the safety profiles of recently approved agents. In addition, 90% of clinical pharmacists reported skill gaps weighing the risks and benefits of treating patients with immuno-oncology agents while affected by lupus. Finally, patient communication challenges were identified: HCPs reported difficulties discussing essential aspects of immunotherapy to patients as well as how they might compare to other types of therapies. Conclusion The challenges highlighted in this study reveal substantial educational gaps related to the integration of immuno-oncology agents into practice for various groups of HCPs. These findings provide a strong base of evidence for future educational initiatives.

PurposeA recently published phase 2 neoadjuvant trial in patients with early-stage non-small cell lung cancer (NSCLC) (NCT02818920) evaluated the potential efficacy of pembrolizumab administration in the absence of chemotherapy. This communication reports on conventional and distribution-based immune profiling efforts in efforts to identify novel biomarkers predictive of benefit.MethodsPatients with stage 1B-3A NSCLC received two cycles of pembrolizumab (P), followed by surgical resection of the remaining tumors (NCT02818920). Banked peripheral blood mononuclear cells (PBMCs) were analyzed at baseline and following the second dose of P. Resected tumors were disaggregated, and cells were viably cryopreserved. Based on pathologic examination of the tumors, patients were categorized as major pathologic responders (MPR; ≤10% viable tumor present), or non-MPR (>10% viable tumor present). High-parameter immune phenotyping by flow cytometry was performed on all available tumor and PBMC specimens, and results were expressed using both conventional phenotypic frequency analyses as well as a novel distribution-based biomarker identification strategy aimed at discovery of patterns associated with MPR.ResultsConventional, frequency-based flow cytometric immune phenotyping of participant tumor microenvironments and PBMC revealed several MPR-associated trends, only a few of which reached statistical significance. The distribution-based biomarker identification strategy greatly enhanced the discovery of statistically significant cell types and patterns of change associated with MPR.ConclusionsThis novel, distribution-based analytic framework identified MPR-associated immune cell subsets in baseline PBMC that were not evident using conventional frequency-based immune profiling. Profiling the microenvironment of MPR-associated tumors revealed statistically significant distributional differences among highly expressed cellular markers on CD8+ cells.

BackgroundMEM-288 is a conditionally replicative oncolytic adenovirus expressing human IFNβ and a recombinant membrane-stable form of CD40L (MEM40). Preclinical studies show MEM-288 induces robust dendritic cell (DC)-mediated systemic T-cell responses capable of inhibiting injected and abscopal tumor growth.Methods14 patients with metastatic NSCLC refractory to anti-PD(L)1 and platinum chemotherapy (median 4 prior lines of treatment) received MEM-288 intratumoral treatment every 3 weeks in the same lesion for up to 6 cycles (NCT05076760). We collected peripheral blood at serial timepoints and obtained tumor biopsies prior to the 1st and 2nd injections. We evaluated associations (t-test) between clinical outcomes in injected and non-injected tumors with pre- and on-treatment tumor microenvironment (TME) immune cell composition, plasma cytokines, T-cell clonotypes, and neoantigen-reactive T-cells.ResultsInterventional radiologists successfully injected MEM-288 into superficial tumors (n=7) and deep visceral tumors (n=7), including liver (n=4) and lung (n=2). Treatment-related AEs (all ≤13%) were limited to grade 1–2 injection site reactions and flu-like symptoms. We collected matched pre- and on-treatment biopsies of the injected lesion from 12 patients. Pre-treatment presence of T-cells and conventional DC1 in tumors significantly associated (p < 0.05) with subsequent shrinkage of injected tumors (n=5 of 11 {45%}). MEM-288 generated systemic anti-tumor T-cell immunity in responding patients as demonstrated by cytokine, T-cell clonotype, and tumor neoantigen analysis. Patient 002-001 (53% tumor shrinkage) showed both a marked increase in T-cell clonotypes present in the injected tumor and increases in tumor neoantigen-reactive peripheral T-cells. Remarkably, this patient has a subsequent ongoing complete response in multiple extracranial tumors 14 months after taxane/anti-VEGF rechallenge. Patient 002-005 (40% tumor shrinkage) showed increased plasma cytokines on-treatment, including IFNγ (131-fold increase; p < 0.05), and subsequently developed a partial response (7 months) to carboplatin/etoposide rechallenge. Patient 002-012 (28% tumor shrinkage) had pseudo-progression with initial increase in a non-injected distant tumor lymph node followed by subsequent shrinkage and meaningful disease control (ongoing SD at 4 months). Tumor shrinkage was limited to the 5 patients with ≤3 prior lines of treatment.ConclusionsMEM-288 injection shrank tumors in 45% of evaluable NSCLC patients. Although no RECIST responses were yet met, tumor shrinkage associated with an immune-active TME in the injected tumors, systemic immune response activation, and strong benefit to chemotherapy rechallenge and long-term disease control. These proof-of-concept results guided the design of an expansion study of MEM-288 with nivolumab for second-line treatment of metastatic NSCLC refractory to anti-PD(L)1 ± chemotherapy.Trial RegistrationClinicaltrials.gov ID: NCT05076760Ethics ApprovalThe studies described received IRB approval (Moffitt: Adverra IRB, # Pro00060205, Duke: DUHS IRB, #Pro00109517) prior to commencement, and in the clinical trial described all participants provided written informed consent before taking part.

Purpose Preclinical data suggest concurrent inhibition of VEGF, mTOR and EGFR pathways may augment antitumor and antiangiogenic effects compared to inhibition of each pathway alone. This study evaluated the maximum tolerated dose/recommended phase II dose and safety and tolerability of bevacizumab, everolimus and panitumumab drug combination. Methods Subjects with advanced solid tumors received escalating doses of everolimus and flat dosing of panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. Dose-limiting toxicities (DLTs) were assessed in cycle 1; toxicity evaluation was closely monitored throughout treatment. Treatment continued until disease progression or undesirable toxicity. Results Thirty-two subjects were evaluable for toxicity; 31 subjects were evaluable for tumor response. DLTs were observed in cohorts with everolimus at 10 and 5 mg daily and included grade 3 mucositis, skin rash and thrombocytopenia. Therefore, everolimus was dose-reduced to 5 mg three times weekly, which improved the tolerability of the treatment regimen. Common adverse events were skin rash/pruritus (91 %), mucositis/stomatitis (75 %), hypomagnesemia (72 %), hypocalcemia (56 %) and hypokalemia (50 %). There were 3 partial responses; an additional 10 subjects had stable disease ≥6 months. Three subjects with ovarian cancer and one with endometrial cancer achieved prolonged disease control ranging from 11 to >40 months. Conclusions The recommended phase II dose is everolimus at 5 mg three times weekly plus panitumumab at 4.8 mg/kg and bevacizumab at 10 mg/kg every 2 weeks. This dosing regimen has an acceptable safety and tolerability profile and appears to have moderate the clinical activity in refractory tumors.

In a randomized study involving 582 patients with advanced nonsquamous lung cancer that had progressed after primary treatment, nivolumab produced a higher response rate and longer overall survival than standard docetaxel. Effective options are limited for patients with nonsquamous non–small-cell lung cancer (NSCLC) whose disease progresses after first-line chemotherapy. Docetaxel was approved as a second-line treatment for advanced NSCLC on the basis of longer survival than that with best supportive care. 1 – 3 Newer agents, such as pemetrexed and erlotinib, which have a better side-effect profile than docetaxel, have either been shown to be noninferior to docetaxel or have failed to show superiority to docetaxel with respect to overall survival when they are used as second-line therapy. 4 , 5 The programmed death 1 (PD-1) receptor expressed on activated T cells is engaged by . . .

Cytometry data, including flow cytometry and mass cytometry, are now standard in numerous immunological studies, such as cancer immunotherapy and vaccine trials. These data enable the monitoring of an individual's peripheral immune status over time, providing detailed insights into immune cells and their role in clinical outcomes. However, traditional analyses relying on summary statistics, such as cell subset proportions and mean fluorescence intensity, may overlook critical single-cell information. To address this limitation, we introduce cytoGPNet, a novel approach that harnesses extensive cytometry data to predict individual-level outcomes. cytoGPNet is designed to address four key challenges: (1) accommodating varying numbers of cells per sample; (2) analyzing the longitudinal cytometry data to understand temporal relationships; (3) maintaining robustness under the constraints of limited individual samples in immunological studies; and (4) ensuring interpretability to facilitate biomarker identification. We apply cytoGPNet to data from multiple diverse studies, each with unique characteristics. Despite these differences, cytoGPNet consistently outperforms other popular methods in terms of prediction accuracy. Moreover, cytoGPNet provides interpretable results at multiple levels, offering valuable insights. Our findings underscore the effectiveness and versatility of cytoGPNet in enhancing the analysis of cytometry data and its potential to advance immunological research.