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Summary Background Both innate and adaptive immune responses are important components of anticancer immunity. The CD47–SIRPα interaction could represent an important pathway used by tumour cells to evade immune surveillance. We aimed to evaluate the safety, pharmacokinetics, pharmacodynamics, and anticancer activity of evorpacept (also known as ALX148), a high-affinity CD47-blocking protein with an inactive IgG Fc region in patients with solid tumours. Methods We did a first-in-human, open-label, multicentre, phase 1 dose-escalation and dose-expansion study at nine hospitals and one clinic in the USA and Korea. Eligible patients for the dose-escalation and safety lead-in phases were aged 18 years or older with histological or cytological diagnosis of advanced or metastatic solid tumours with no available standard therapy, measurable or unmeasurable disease according to the Response Evaluation Criteria in Solid Tumors version 1.1, and an Eastern Cooperative Oncology Group performance status score of 0 or 1. In the dose-escalation phase, which used a 3 + 3 design, patients received intravenous evorpacept at either 0·3, 1, 3, or 10 mg/kg once per week in 21-day cycles, or 30 mg/kg once every other week in 28-day cycles. In the safety lead-in phase, patients were given the maximum tolerable dose of evorpacept from the dose-escalation phase plus either intravenous pembrolizumab (200 mg administered once every 3 weeks) or intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks). In the dose-expansion phase, additional patients aged 18 years or older with second-line or later-line advanced malignancies were enrolled into three parallel cohorts: those with head and neck squamous cell carcinoma (HNSCC) and those with non-small-cell lung cancer (NSCLC) were given the maximum tolerated dose of evorpacept plus intravenous pembrolizumab (200 mg administered once every 3 weeks), and patients with HER2-positive gastric or gastroesophageal junction cancer were given the maximum tolerated dose of evorpacept plus intravenous trastuzumab (8 mg/kg loading dose followed by 6 mg/kg once every 3 weeks) until disease progression, voluntary withdrawal from the study, or unacceptable toxicity. The primary endpoint was the maximum tolerated dose of evorpacept administered as a single agent and in combination with pembrolizumab or trastuzumab, measured by the occurrence of dose-limiting toxicities during the first cycle, and was assessed in all patients who had received at least one dose of evorpacept. Secondary outcomes included the safety, tolerability, and antitumour activity of evorpacept, alone or in combination with pembrolizumab or trastuzumab. The primary outcome, safety, and tolerability were assessed in all patients who had received at least one dose of evorpacept, and antitumour activity was assessed in those who recieved at least one dose of study treatment and underwent at least one post-baseline tumor assessment. This trial is registered with ClinicalTrials.gov , NCT03013218 . Findings Between March 6, 2017, and Feb 21, 2019, 110 patients received single-agent evorpacept (n=28), evorpacept plus pembrolizumab (n=52), or evorpacept plus trastuzumab (n=30), and were included in the safety analysis. Median follow-up was 29·1 months (95% CI not calculable [NC]–NC) in the single-agent cohort, 27·0 months (25·1–28·8) in the evorpacept plus pembrolizumab cohort, and 32·7 months (27·0–32·7) in the evorpacept plus trastuzumab cohort. Two (7%) dose-limiting toxicities in the first cycle were reported in patients who received single-agent evorpacept; neutropenia with an associated infection in one patient with gastroesophageal junction cancer who received 3 mg/kg once per week, and thrombocytopenia with associated bleeding in one patient with pancreatic cancer who received 30 mg/kg once every other week. No maximum tolerated dose was reached; the maximum administered doses were 10 mg/kg once per week or 30 mg/kg once every other week. The 10 mg/kg once per week dose was used in the expansion cohorts in combination with pembrolizumab or trastuzumab. The most common grade 3 or worse treatment-related adverse events were thrombocytopenia with single-agent evorpacept (two [7%] patients) and evorpacept plus pembrolizumab (two [4%]), and thrombocytopenia (two [7%]) and neutropenia (two [7%]) with evorpacept plus trastuzumab. In patients who received single-agent evorpacept, four treatment-related serious adverse events were reported. Five serious treatment-related adverse events related to evorpacept plus pembrolizumab were reported, and one serious adverse event related to evorpacept plus trastuzumab was reported. In response-evaluable patients in the dose-escalation phase (n=15) receiving single-agent evorpacept once per week, four (27%) had a best overall response of stable disease (two received 0·3 mg/kg, one received 3 mg/kg, and one received 10 mg/kg); in the 11 patients who received single-agent evorpacept at the highest dose of 30 mg/kg once every other week, two (18%) had stable disease. In the dose-expansion cohort, overall responses were recorded in four (20·0%; 95% CI 5·7–43·7) of 20 patients with HNSCC who received evorpacept plus pembrolizumab, in one (5·0%; 0·1–24·9) of 20 patients with NSCLC who received evorpacept plus pembrolizumab, and in four (21·1%; 6·1–45·6) of 19 patients with gastric or gastroesophageal junction cancer who received evorpacept plus trastuzumab. Interpretation The safety findings support the use of evorpacept in combination with pembrolizumab or trastuzumab for patients with advanced solid tumours. Preliminary antitumour activity results support future investigation of evorpacept combined with pembrolizumab or trastuzumab in patients with HNSCC, gastric or gastroesophageal junction cancer, and NSCLC. Funding ALX Oncology.

Acquired resistance (AR) to programmed cell death protein 1/programmed death-ligand 1 [PD-(L)1] blockade is frequent in non-small-cell lung cancer (NSCLC), occurring in a majority of initial responders. Patients with AR may have unique properties of persistent antitumor immunity that could be re-harnessed by investigational immunotherapies. The absence of a consistent clinical definition of AR to PD-(L)1 blockade and lack of uniform criteria for ensuing enrollment in clinical trials remains a major barrier to progress; such clinical definitions have advanced biologic and therapeutic discovery. We examine the considerations and potential controversies in developing a patient-level definition of AR in NSCLC treated with PD-(L)1 blockade. Taking into account the specifics of NSCLC biology and corresponding treatment strategies, we propose a practical, clinical definition of AR to PD-(L)1 blockade for use in clinical reports and prospective clinical trials. Patients should meet the following criteria: received treatment that includes PD-(L)1 blockade; experienced objective response on PD-(L)1 blockade (inclusion of a subset of stable disease will require future investigation); have progressive disease occurring within 6 months of last anti-PD-(L)1 antibody treatment or rechallenge with anti-PD-(L)1 antibody in patients not exposed to anti-PD-(L)1 in 6 months.

BACKGROUND: With increasing anti-PD-1 therapy use in patients with melanoma and other tumor types, there is interest in developing early on-treatment biomarkers that correlate with long-term patient outcome. An understanding of the pathologic features of immune-mediated tumor regression is key in this endeavor. MATERIALS AND METHODS: Histologic features of immune-related pathologic response (irPR) following anti-PD-1 therapy were identified on hematoxylin and eosin (H&E)-stained slides in a discovery cohort of pre- and on-treatment specimens from n = 16 patients with advanced melanoma. These features were used to generate an irPR score [from 0 = no irPR features to 3 = major pathologic response on biopsy (MPR(bx), ≤10% residual viable tumor)]. This scoring system was then tested for an association with objective response by RECIST1.1 and overall survival in a prospectively collected validation cohort of pre- and on-treatment biopsies (n = 51 on-treatment at 4-week timepoint) from melanoma patients enrolled on the nivolumab monotherapy arm of CA209-038 (NCT01621490). RESULTS: Specimens from responders in the discovery cohort had features of immune-activation (moderate–high TIL densities, plasma cells) and wound-healing/tissue repair (neovascularization, proliferative fibrosis) compared to nonresponders, (P ≤ 0.021, for each feature). In the validation cohort, increasing irPR score associated with objective response (P = 0.009) and MPR(bx) associated with increased overall survival (n = 51; HR 0.13; 95%CI, 0.054–0.31, P = 0.015). Neither tumoral necrosis nor pretreatment histologic features were associated with response. Eight of 16 (50%) of patients with stable disease showed irPR features, two of which were MPR(bx), indicating a disconnect between pathologic and radiographic features at the 4-week on-therapy timepoint for some patients. CONCLUSIONS: Features of immune-mediated tumor regression on routine H&E-stained biopsy slides from patients with advanced melanoma correlate with objective response to anti-PD-1 and overall survival. An on-therapy biopsy may be particularly clinically useful for informing treatment decisions in patients with radiographic stable disease. This approach is inexpensive, straightforward, and widely available.

Long-term survival outcomes among melanoma patients with brain metastases treated with immune checkpoint inhibitors are limited. In this retrospective study at 2 centers, metastatic melanoma patients with radiographic evidence of brain metastases who received anti-programmed death-1 (PD-1) monotherapy or nivolumab in combination with ipilimumab between 2014 and 2017 were included. Overall survival (OS) was assessed in diagnosis-specific graded prognostic assessment (ds-GPA) and melanoma-molecular graded prognostic assessment (molGPA) prognostic risk groups. Baseline clinical covariates were used to identify predictors of OS in univariate/multivariable Cox proportional-hazards models. A total of 84 patients (58 monotherapy, 26 combination) were included with a median duration of follow-up of 43.4 months (maximum: 5.1 y). The median OS [95% confidence interval (CI)] was 3.1 months (1.8, 7) for ds-GPA 0-1, 22.1 months [5.4, not reached (NR)] for ds-GPA 2 and NR (24.9, NR) for ds-GPA 3-4 in the monotherapy cohort [hazard ratio (HR) for ds-GPA 3-4 vs. 0-1: 0.13 (95% CI: 0.052, 0.32); 0.29 (95% CI: 0.12, 0.63) for ds-GPA 2 vs. 0-1]. The median OS was 1.1 months (95% CI: 0.3, NR) for ds-GPA 0-1, 11.8 months (95% CI: 2.9, 23.3) for ds-GPA 2 and 24.4 months (95% CI: 3.4, NR) for ds-GPA 3-4 in the combination cohort [HR for 3-4 vs. 0-1: 0.013 (95% CI: 0.0012, 0.14); HR for ds-GPA 2 vs. 0-1: 0.033 (0.0035, 0.31)]. Predictors associated with longer survival included ds-GPA or molGPA1 (among prognostic indices), neutrophil-to-lymphocyte ratio (4 vs. ≥4), while high lactate dehydrogenase, neurological symptoms, and leptomeningeal metastases were associated with shorter survival. Baseline ds-GPA/molGPA1 and neutrophil-to-lymphocyte ratio4 were strong predictors of long-term survival to anti-PD-1-based immune checkpoint inhibitors in melanoma brain metastases patients previously naive to anti-PD-1 therapy in a real-world clinical setting treated at independent centers.

SNF'ing out antitumor immunity Immune checkpoint inhibitors induce durable tumor regressions in some, but not all, cancer patients. Understanding the mechanisms that determine tumor sensitivity to these drugs could potentially expand the number of patients who benefit (see the Perspective by Ghorani and Quezada). Pan et al. discovered that tumor cells in which a specific SWI/SNF chromatin remodeling complex had been experimentally inactivated were more sensitive to T cell–mediated killing. The cells were more responsive to interferon-γ, leading to increased secretion of cytokines that promote antitumor immunity. Miao et al. examined the genomic features of tumors from patients with metastatic renal cell carcinoma who had been treated with immune checkpoint inhibitors. Tumors harboring inactivating mutations in PBRM1 , which encodes a subunit of the same SWI/SNF complex, were more likely to respond to the drugs. Science , this issue p. 770 , p. 801 ; see also p. 745

Introduction Nous avions precedemment rapporte l’efficacite et la tolerance de NIVO + IPI chez des patients (pts) atteints d’un melanome et presentant des metastases cerebrales (MBM) non traitees et asymptomatiques, de l’etude CheckMate 204. Nous presentons ici la premiere analyse de NIVO + IPI chez des patients atteints de MBM symptomatiques, ainsi que des donnees mises a jour dans la cohorte de pts presentant des MBM asymptomatiques. Materiel et methodes Dans cet essai de phase II, des patients presentant ≥ 1 MBM mesurable, non irradiee et de 0,5 a 3,0 cm ont ete inclus dans 2 cohortes : – ceux ne presentant aucun symptome neurologique et ne recevant pas de traitement par corticosteroides (asymptomatiques ; cohorte A) ; – ceux presentant des symptomes neurologiques, qu’ils recoivent ou non un traitement par corticosteroides (symptomatiques ; cohorte B). Dans les deux cohortes, les pts ont recu NIVO 1 mg/kg + IPI 3 mg/kg toutes les 3 semaines × 4, puis NIVO 3 mg/kg toutes les 2 semaines jusqu’a progression ou toxicite. Le critere d’evaluation principal etait le taux de benefice clinique intracrânien (CBR ; proportion de patients avec une reponse complete [CR] + reponse partielle [PR] + maladie stable [SD] ≥ 6 mois). A la date limite clinique du 1er mai 2018, tous les patients traites (101 dans la cohorte A et 18 dans la cohorte B) avaient ete suivis pendant ∼6 mois ou plus. Resultats Dans cette analyse actualisee de la cohorte A (suivi median de 20,6 mois), le CBR etait de 58,4 % (voir Tableau 1 ). Dans la cohorte B, les patients ont recu une mediane de 1 dose de NIVO + IPI, et 2 patients sur 18 (11 %) ont recu les 4 doses. Apres un suivi median de 5,2 mois dans la cohorte B, le taux de reponse objective intracrânienne etait de 16,7 % et le CBR de 22,2 %. Des evenements indesirables de grade 3/4 ont ete observes chez 54,5 % des patients de la cohorte A et chez 55,6 % de ceux de la cohorte B (6,9 % et 16,7 % touchant le systeme nerveux, respectivement), avec 1 deces lie au traitement dans la cohorte A (myocardite immuno-induite). Conclusion Chez les patients atteints de MBM asymptomatiques, ces resultats actualises montrent un taux eleve de reponses intracrâniennes durables, ce qui conforte NIVO + IPI en tant que traitement de premiere intention dans cette population. Une activite anti-tumorale intracrânienne a ete observee avec NIVO + IPI chez les patients atteints de MBM symptomatiques, mais des etudes supplementaires sont necessaires pour comprendre les mecanismes biologiques de la resistance a l’immunotherapie et pour ameliorer les traitements dans cette population difficile.

Background Pembrolizumab demonstrated robust antitumor activity and safety in the phase Ib KEYNOTE-001 study (NCT01295827) of advanced melanoma. Five-year outcomes in all patients and treatment-naive patients are reported herein. Patients whose disease progressed following initial response and who received a second course of pembrolizumab were also analyzed. Patients and methods Patients aged ≥18 years with previously treated or treatment-naive advanced/metastatic melanoma received pembrolizumab 2 mg/kg every 3 weeks, 10 mg/kg every 3 weeks, or 10 mg/kg every 2 weeks until disease progression, intolerable toxicity, or patient/investigator decision to withdraw. Kaplan–Meier estimates of overall survival (OS) and progression-free survival (PFS) were calculated. Objective response rate and PFS were based on immune-related response criteria by investigator assessment (data cut-off, September 1, 2017). Results KEYNOTE-001 enrolled 655 patients with melanoma; median follow-up was 55 months. Estimated 5-year OS was 34% in all patients and 41% in treatment-naive patients; median OS was 23.8 months (95% CI, 20.2–30.4) and 38.6 months (95% CI, 27.2–not reached), respectively. Estimated 5-year PFS rates were 21% in all patients and 29% in treatment-naive patients; median PFS was 8.3 months (95% CI, 5.8–11.1) and 16.9 months (95% CI, 9.3–35.5), respectively. Median response duration was not reached; 73% of all responses and 82% of treatment-naive responses were ongoing at data cut-off; the longest response was ongoing at 66 months. Four patients [all with prior response of complete response (CR)] whose disease progressed during observation subsequently received second-course pembrolizumab. One patient each achieved CR and partial response (after data cut-off). Treatment-related AEs (TRAEs) occurred in 86% of patients and resulted in study discontinuation in 7.8%; 17% experienced grade 3/4 TRAE. Conclusions This 5-year analysis of KEYNOTE-001 represents the longest follow-up for pembrolizumab to date and confirms the durable antitumor activity and tolerability of pembrolizumab in advanced melanoma. Clinical Trial Registry ClinicalTrials.gov, NCT01295827.

BACKGROUND Nivolumab plus ipilimumab or nivolumab alone resulted in longer progression-free and overall survival than ipilimumab alone in a trial involving patients with advanced melanoma. We now report 5-year outcomes in the trial. METHODS We randomly assigned patients with previously untreated advanced melanoma to receive one of the following regimens: nivolumab (at a dose of 1 mg per kilogram of body weight) plus ipilimumab (3 mg per kilogram) every 3 weeks for four doses, followed by nivolumab (3 mg per kilogram every 2 weeks); nivolumab (3 mg per kilogram every 2 weeks) plus ipilimumab-matched placebo; or ipilimumab (3 mg per kilogram every 3 weeks for four doses) plus nivolumab-matched placebo. The two primary end points were progression-free survival and overall survival in the nivolumab-plus-ipilimumab group and in the nivolumab group, as compared with the ipilimumab group. RESULTS At a minimum follow-up of 60 months, the median overall survival was more than 60.0 months (median not reached) in the nivolumab-plus-ipilimumab group and 36.9 months in the nivolumab group, as compared with 19.9 months in the ipilimumab group (hazard ratio for death with nivolumab plus ipilimumab vs. ipilimumab, 0.52; hazard ratio for death with nivolumab vs. ipilimumab, 0.63). Overall survival at 5 years was 52% in the nivolumab-plus-ipilimumab group and 44% in the nivolumab group, as compared with 26% in the ipilimumab group. No sustained deterioration of health-related quality of life was observed during or after treatment with nivolumab plus ipilimumab or with nivolumab alone. No new late toxic effects were noted. CONCLUSIONS Among patients with advanced melanoma, sustained long-term overall survival at 5 years was observed in a greater percentage of patients who received nivolumab plus ipilimumab or nivolumab alone than in those who received ipilimumab alone, with no apparent loss of quality of life in the patients who received regimens containing nivolumab. (Funded by Bristol-Myers Squibb and others; CheckMate 067 ClinicalTrials.gov number, NCT01844505.).

Background Approved first-line treatments for patients with BRAF V600–mutant advanced melanoma include nivolumab (a programmed cell death protein 1 inhibitor) plus ipilimumab (a cytotoxic T lymphocyte antigen-4 inhibitor; NIVO+IPI) and the BRAF/MEK inhibitors dabrafenib plus trametinib (DAB+TRAM), encorafenib plus binimetinib (ENCO+BINI), and vemurafenib plus cobimetinib (VEM+COBI). Results from prospective randomized clinical trials (RCTs) comparing these treatments have not yet been reported. This analysis evaluated the relative efficacy and safety of NIVO+IPI versus DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma using a matching-adjusted indirect comparison (MAIC). Patients and methods A systematic literature review identified RCTs for DAB+TRAM, ENCO+BINI, and VEM+COBI in patients with BRAF-mutant advanced melanoma. Individual patient-level data for NIVO+IPI were derived from the phase III CheckMate 067 trial (BRAF-mutant cohort) and restricted to match the inclusion/exclusion criteria of the comparator trials. Treatment effects for overall survival (OS) and progression-free survival (PFS) were estimated using Cox proportional hazards and time-varying hazard ratio (HR) models. Safety outcomes (grade 3 or 4 treatment-related adverse events) with NIVO+IPI and the comparators were compared. Results In the Cox proportional hazards analysis, NIVO+IPI showed improved OS compared with DAB+TRAM (HR = 0.53; 95% confidence interval [CI], 0.39-0.73), ENCO+BINI (HR = 0.60; CI, 0.42-0.85), and VEM+COBI (HR = 0.50; CI, 0.36-0.70) for the overall study period. In the time-varying analysis, NIVO+IPI was associated with significant improvements in OS and PFS compared with the BRAF/MEK inhibitors 12 months after treatment initiation. There were no significant differences between NIVO+IPI and BRAF/MEK inhibitor treatment from 0 to 12 months. Safety outcomes favored DAB+TRAM over NIVO+IPI, whereas NIVO+IPI was comparable to VEM+COBI. Conclusion Results of this MAIC demonstrated durable OS and PFS benefits for patients with BRAF-mutant advanced melanoma treated with NIVO+IPI compared with BRAF/MEK inhibitors, with the greatest benefits noted after 12 months., Highlights • First-line treatments for BRAF V600-mutant melanoma include NIVO+IPI and BRAF/MEK inhibitors. • Results from prospective RCTs comparing NIVO+IPI and BRAF/MEK inhibitors have not yet been reported. • This MAIC evaluated NIVO+IPI versus BRAF/MEK inhibitors for BRAF-mutant advanced melanoma. • OS and PFS benefits were noted with NIVO+IPI versus BRAF/MEK inhibitors beginning at 12 months. • These findings may provide information relevant to the selection of treatments for BRAF-mutant advanced melanoma.

Background: Inhibition of immune-checkpoint targets including PD1 is clinically effective in a variety of cancers. However, only a subset of patients respond and complete response remains uncommon. To understand the mechanisms of response and resistance, recent studies have focused on neoantigens, copy-number alterations, and transcriptional signatures of tumor tissues collected from patients treated with immune-checkpoint inhibitors. Given the known role of metabolites in modulating immunity, we sought to understand how individual patients' metabolic activities adapt to PD1 immune checkpoint blockade and how they associate with therapeutic benefits. Methods: We profiled 106-202 metabolites in pre- and multiple on-treatment patient serum samples from three independent immunotherapy trials using liquid chromatography-mass spectrometry. These metabolites are involved in the metabolism of amino acids, nucleotides, nitrogen, and lipids, among others. Our study consisted of two Phase 1 trials (CA209-038 and -009) which included 78 patients with advanced melanoma and 91 patients with metastatic renal cell carcinoma (RCC) treated with nivolumab. RNASeq was performed on matched pre- and on-treatment tumor biopsies from the melanoma cohort. To investigate the generalizability of our results, we also performed metabolomics and serum specimens from a large randomized Phase 3 trial (CheckMate 025) with 743 RCC patients, among which 394 received nivolumab and 349 received everolimus. Results: During treatment with nivolumab, kynurenine, a product of tryptophan catabolism and the IDO/TDO genes, was the most significantly changed metabolite at week 4 and at week 6 compared to pre-treatment levels among melanoma patients (37% and 34% increase on average, q=1 × 10-10 and q=1 × 10-8 respectively, paired t-test). By using Kyn/Trp (Kynurenine/Tryptophan) as a metric indicating tryptophan-kynurenine conversion, we found that this ratio falls in a range spanning approximately 8-fold among these patients, suggesting prominent individual-to-individual differences. Specifically, 78% patients had any increases and 26.5% patients had increases above 50% at week 4. We confirmed this significant kynurenine up-regulation following nivolumab treatment in RCC patients in the phase 1 and phase 3 trials. In particular, the phase 3 cohort showed 23% and 24% increase on average at week 4 and week 8 respectively (q=1 × 10-10 and q=1 × 10-12, paired t-test). Additionally, 69.4% and 8.2% patients had Kyn/Trp increases above zero and 50% respectively at week 4. Notably, patients receiving everolimus control treatment had a decrease in kynurenine (q=1 × 10-5, t-test). Kynurenine is synthesized during tryptophan catabolism by indoleamine-2,3-dioxygenase (IDO) or tryptophan dioxygenase (TDO), and has been shown to suppress anti-tumor immune responses. To explore whether the circulating Kyn/Trp correlates with immune-suppression in the tumor microenvironment, we analyzed RNAseq data of matched tumor biopsies from the CA209-038 melanoma trial. We found a significant correlation between the Kyn/Trp ratio and PD-L1 expression, 4 weeks after starting nivolumab treatment (Pearson, p=0.01). We also discovered a correlation between Kyn/Trp and IDO1 but not TDO mRNA levels at the same time point. In contrast, Kyn/Trp was not associated with prior anti-CTLA4 treatment, or tumor mutational load. Moreover, compared to all other metabolites, increases of the Kyn/Trp ratio in the melanoma cohort (week 4 vs baseline) were consistently associated with greater risks for death (p=1.2*10-4, HR=2.71, 95% CI, 1.63-4.51). In particular, patients with a >50% increase in Kyn/Trp had a median OS of 15.7 months while those with decreases had a median survival time of > 38 months (p = 6.0*10-5, log-rank test). In contrast, the baseline Kyn/Trp ratio did not significantly associate with the melanoma patients' overall survival. To confirm this result, the association between Kyn/Trp ratios and overall survival in the larger phase 3 trial in RCC (CheckMate 025) was evaluated using serum samples collected at different time points. We found that at baseline, higher Kyn/Trp ratios associated with shorter overall survival both for the nivolumab- and the everolimus-treated patients (p = 3.6*10-4, HR=1.79, 95% CI, 1.30-2.47; p = 1.7*10-5, HR=2.06, 95% CI, 1.48-2.85; Cox model). However, at week 4, Kyn/Trp significantly associated with overall survival only in the nivolumab arm (p = 4.7*10-4, HR=2.81, 95% CI, 1.57-5.01; Cox model) but not in the everolimus arm (p = 0.53, HR=0.76, 95% CI, 0.32-1.78; Cox model). For nivolumab-treated RCC patients, those with a >50% increases of Kyn/Trp had a median survival of 16.7 months while those with any Kyn/Trp decreases had a median survival of 31.3 months (p = 4.3*10-4, log-rank test).Conclusions: We identified increased tryptophan to kynurenine conversion in response to PD1 blockade in a subset of melanoma and RCC patients. By using independent cohorts, we showed that Kyn/Trp temporal alterations robustly correlated with overall survival of patients receiving nivolumab. Our findings illustrate that checkpoint blockade in combination with IDO/TDO inhibitors might only benefit a selected group of patients with checkpoint-inhibition-triggered kynurenine pathway activation. Given the lack of improved therapeutic outcomes with PD1 and selective IDO1 inhibition among unselected patient populations in a recent phase 3 trial, our findings highlight the need and feasibility of patient stratification by monitoring serum Kyn/Trp alterations, show that kynurenine signaling may still be a relevant therapeutic target and more generally point to the relevance of metabolic adaptations in cancer immunotherapy. Our findings highlight the need and feasibility of patient stratification by monitoring serum Kyn/Trp alterations and point to the relevance of metabolic adaptations in cancer immunotherapy. Citation Format: Haoxin Li, Kevin Bullock, Carino Gurjao, David Braun, Sachet A. Shukla, Dominick Bosse, Aly-Khan A. Lalani, Shuba Gopal, Chelsea Jin, Christine Horak, Megan Wind-Rotolo, Sabina Signoretti, David F. McDermott, Gordon J. Freeman, Eliezer M. Van Allen, Stuart L. Schreiber, Frank Stephen Hodi, William R. Sellers, Levi A. Garraway, Clary B. Clish, Toni K. Choueiri, Marios Giannakis. Metabolomic adaptations and correlates of survival to immune checkpoint blockade [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr NG13.

Previously reported results from the phase 3 CheckMate 067 trial showed a significant improvement in objective responses, progression-free survival, and overall survival with nivolumab plus ipilimumab or nivolumab alone compared with ipilimumab alone in patients with advanced melanoma. The aim of this report is to provide 4-year updated efficacy and safety data from this study.In this phase 3 trial, eligible patients were aged 18 years or older with previously untreated, unresectable, stage III or stage IV melanoma, known BRAFBetween July 3, 2013, and March 31, 2014, 945 patients were enrolled and randomly assigned to nivolumab plus ipilimumab (n=314), nivolumab (n=316), or ipilimumab (n=315). Median follow-up was 46·9 months (IQR 10·9-51·8) in the nivolumab plus ipilimumab group, 36·0 months (10·5-51·4) in the nivolumab group, and 18·6 months (7·6-49·5) in the ipilimumab group. At a minimum follow-up of 48 months from the date that the final patient was enrolled and randomised, median overall survival was not reached (95% CI 38·2-not reached) in the nivolumab plus ipilimumab group, 36·9 months (28·3-not reached) in the nivolumab group, and 19·9 months (16·9-24·6) in the ipilimumab group. The hazard ratio for death for the combination versus ipilimumab was 0·54 (95% CI 0·44-0·67; p0·0001) and for nivolumab versus ipilimumab was 0·65 (0·53-0·79; p0·0001). Median progression-free survival was 11·5 months (95% CI 8·7-19·3) in the nivolumab plus ipilimumab group, 6·9 months (5·1-10·2) in the nivolumab group, and 2·9 months (2·8-3·2) in the ipilimumab group. The hazard ratio for progression-free survival for the combination versus ipilimumab was 0·42 (95% CI 0·35-0·51; p0·0001) and for nivolumab versus ipilimumab was 0·53 (0·44-0·64; p0·0001). Treatment-related grade 3-4 adverse events were reported in 185 (59%) of 313 patients who received nivolumab plus ipilimumab, 70 (22%) of 313 who received nivolumab, and 86 (28%) of 311 who received ipilimumab. The most common treatment-related grade 3 adverse events were diarrhoea in the nivolumab plus ipilimumab group (29 [9%] of 313) and in the nivolumab group (nine [3%] of 313) and colitis in the ipilimumab group (23 [7%] of 311); the most common grade 4 adverse event in all three groups was increased lipase (15 [5%] of 313 in the combination group, ten [3%] of 313 in the nivolumab group, and four [1%] of 311 in the ipilimumab group). Serious adverse events were not analysed for the 4-year follow-up. In total for the study, there were four treatment-related deaths: two in the nivolumab plus ipilimumab group (one cardiomyopathy and one liver necrosis), one in the nivolumab group (neutropenia), and one in the ipilimumab group (colon perforation). No additional treatment-related deaths have occurred since the previous (3-year) analysis.The results of this analysis at 4 years of follow-up show that a durable, sustained survival benefit can be achieved with first-line nivolumab plus ipilimumab or nivolumab alone in patients with advanced melanoma.Bristol-Myers Squibb.

Isolation of circulating tumor cells (CTCs) from blood of melanoma patients has been difficult owing to inconsistent expression of surface antigens. Here we report on the isolation, detection, and characterization of CTCs from blood of melanoma patients using microfiltration and fluorescent in-situ hybridization (FISH). Two tubes of blood from 15 patients with advanced melanoma were collected. These two tubes subsequently underwent filtration through a membrane with pore sizes of 7.5 μm. Isolated cells from one tube were analyzed by FISH for RREB1 (6p24), MYB (6q32), SE6 (D6Z1), and CCND1 (11q13) and the other paired specimen was analyzed by immunofluorescence for HMB45, melanoma-associated antigen recognized by T cells-1, tyrosinase and melanogenesis associated transcription factor. We identified CTCs in 10 out of 13 melanoma samples by immunofluorescence (2.5-99 CTCs/3 ml of blood) and in 13 specimens by FISH (7.2-76 CTCs/3 ml of blood) with more CTCs identified by FISH in 10 out 13 samples. Two filters failed. Our results show that CTCs are detectable in the majority of patients with advanced melanoma. These tools will be useful in characterizing treatment related changes of melanoma in CTCs.

Purpose: To examine the onset and outcome of ipilimumab-related hypophysitis and the response to treatment with systemic high-dose corticosteroids (HDS). Experimental Design: Twenty-five patients who developed ipilimumab-related hypophysitis were analyzed for the incidence, time to onset, time to resolution, frequency of resolution, and the effect of systemic HDS on clinical outcome. To calculate the incidence, the total number (187) of patients with metastatic melanoma treated with ipilimumab at Dana-Farber Cancer Institute (DFCI; Boston, MA) was retrieved from the DFCI oncology database. Comparisons between corticosteroid treatment groups were performed using the Fisher exact test. The distributions of overall survival were based on the method of Kaplan–Meier. Results: The overall incidence of ipilimumab-related hypophysitis was 13%, with a higher rate in males (16.1%) than females (8.7%). The median time to onset of hypophysitis after initiation of ipilimumab treatment was 9 weeks (range, 5–36 weeks). Resolution of pituitary enlargement, secondary adrenal insufficiency, secondary hypothyroidism, male secondary hypogonadism, and hyponatremia occurred in 73%, 0%, 64%, 45%, and 92% of patients, respectively. Systemic HDS treatment did not improve the outcome of hypophysitis as measured by resolution frequency and time to resolution. One-year overall survival in the cohort of patients was 83%, and while it was slightly higher in patients who did not receive HDS, there was no statistically significant difference between treatment arms. Conclusion: Systemic HDS therapy in patients with ipilimumab-related hypophysitis may not be indicated. Instead, supportive treatment of hypophysitis-related hormone deficiencies with the corresponding hormone replacement should be given. Clin Cancer Res; 21(4); 749–55. ©2014 AACR.

KEYNOTE-030 (ClinicalTrials.gov ID, NCT02083484) was a global expanded access program that allowed access to pembrolizumab, an antiprogrammed death 1 antibody, for patients with advanced melanoma before its regulatory approval. Patients with unresectable stage III/IV melanoma that progressed after standard-of-care therapy, including ipilimumab and, if BRAFV600 mutant, a BRAF inhibitor, were eligible to receive pembrolizumab 2 mg/kg every 3 weeks. Response was assessed by immune-related response criteria by investigator review. Adverse events (AEs) were graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0. In the United States, 979 patients enrolled between April and September 2014. Of the 947 evaluable patients, 621 (65.6%) remained on treatment and transitioned to receive commercial pembrolizumab following approval by the Food and Drug Administration, whereas 326 (34.4%) discontinued, most commonly for disease progression (39.6%) or death (26.4%). Objective response rate was 14.5% (95% confidence interval, 12.2%–16.8%) in the treated population (n=947) and 22.1% (95% confidence interval, 18.8%–25.5%) in patients who had ≥1 response assessment reported (n=619). Twelve patients achieved complete response. One hundred eighty-one (19.1%) patients experienced ≥1 treatment-related AE, most commonly general disorders (8.0%), skin/subcutaneous tissue disorders (7.3%), and gastrointestinal disorders (6.4%); 29 (3.1%) patients experienced ≥1 grade 3/4 treatment-related AE. Immune-mediated AEs were also reported. There were no treatment-related deaths. The safety and efficacy observed in this expanded access program were consistent with those previously reported for similar populations and support the use of pembrolizumab for patients with advanced melanoma.

Author(s): Guo, J; Carvajal, RD; Dummer, R; Hauschild, A; Daud, A; Bastian, BC; Markovic, SN; Queirolo, P; Arance, A; Berking, C; Camargo, V; Herchenhorn, D; Petrella, TM; Schadendorf, D; Sharfman, W; Testori, A; Novick, S; Hertle, S; Nourry, C; Chen, Q; Hodi, FS | Abstract: BackgroundThe single-arm, phase II Tasigna Efficacy in Advanced Melanoma (TEAM) trial evaluated the KIT-selective tyrosine kinase inhibitor nilotinib in patients with KIT-mutated advanced melanoma without prior KIT inhibitor treatment.Patients and methodsForty-two patients with KIT-mutated advanced melanoma were enrolled and treated with nilotinib 400 mg twice daily. TEAM originally included a comparator arm of dacarbazine (DTIC)-treated patients; the design was amended to a single-arm trial due to an observed low number of KIT-mutated melanomas. Thirteen patients were randomized to DTIC before the protocol amendment removing this study arm. The primary endpoint was objective response rate (ORR), determined according to Response Evaluation Criteria In Solid Tumors.ResultsORR was 26.2% (n = 11/42; 95% CI, 13.9%-42.0%), sufficient to reject the null hypothesis (ORR ≤10%). All observed responses were partial responses (PRs; median response duration, 7.1 months). Twenty patients (47.6%) had stable disease and 10 (23.8%) had progressive disease; 1 (2.4%) response was unknown. Ten of the 11 responding patients had exon 11 mutations, four with an L576P mutation. The median progression-free survival and overall survival were 4.2 and 18.0 months, respectively. Three of the 13 patients on DTIC achieved a PR, and another patient had a PR following switch to nilotinib.ConclusionNilotinib activity in patients with advanced KIT-mutated melanoma was similar to historical data from imatinib-treated patients. DTIC treatment showed potential activity, although the low patient number limits interpretation. Similar to previously reported results with imatinib, nilotinib showed greater activity among patients with an exon 11 mutation, including L576P, suggesting that nilotinib may be an effective treatment option for patients with specific KIT mutations.Clinical trial registrationClinicalTrials.gov, NCT01028222.

As checkpoint inhibitor immunotherapies gain traction among cancer researchers and clinicians, the need grows for assays that can definitively phenotype patient immune cells. Herein, we present an 8-color flow cytometry panel for lineage and immune checkpoint markers and validate it using healthy human donor peripheral blood mononuclear cells (PBMCs). Flow cytometry data was generated on a BD LSR Fortessa and supported by Luminex multiplex soluble immunoassay. Our data showed significant variation between donors at both baseline and different stages of activation, as well as a trend in increasing expression of checkpoint markers on stimulated CD4+ and CD8+ T-cells with time. Soluble immune checkpoint quantification assays revealed that LAG-3, TIM-3, CTLA-4, and PD-1 soluble isoforms are upregulated after stimulation. This 8-color flow cytometry panel, supported here by soluble immunoassay, can be used to identify and evaluate immune checkpoints on T-lymphocytes in cryopreserved human PBMC samples. This panel is ideal for characterizing checkpoint expression in clinical samples for which cryopreservation is necessary.

Introduction L’association de NIVO et d’IPI a ameliore la survie sans progression (SSP) et le taux de reponse objective par rapport a l’IPI seul dans l’essai de phase II CheckMate 069 et l’essai de phase III CheckMate 067 chez des patients atteints de melanome avance naif de traitement. Nous presentons ici les premiers resultats de survie globale (SG) de l’etude CheckMate 067 ( NCT01844505 ). Materiel et methodes Des patients naifs de traitement (n = 945) atteints de melanome avance ont ete randomises selon un ratio 1:1:1 pour recevoir, soit la combinaison NIVO 1 mg/kg + IPI 3 mg/kg toutes les 3 semaines × 4, suivi de NIVO 3 mg/kg toutes les 2 semaines, soit du NIVO 3 mg/kg toutes les 2 semaines + placebo, soit de l’IPI 3 mg/kg toutes les 3 semaines × 4 + placebo, jusqu’a progression ou toxicite inacceptable. Les patients ont ete stratifies selon leur statut PD-L1 ( Resultats Avec un suivi minimum de 28 mois, la SG mediane n’a pas ete atteinte dans les groupes NIVO + IPI ou NIVO, et etait de 20,0 mois pour l’IPI (risque relatif [RR] : NIVO + IPI vs. IPI, 0,55 ; p Conclusion L’association NIVO + IPI et le NIVO seul ont tous deux significativement ameliore la SG, par rapport a l’IPI seul. Dans des analyses descriptives, l’association NIVO + IPI semble montrer des resultats de survie plus favorables par rapport au NIVO seul, notamment dans des sous-groupes cliniquement pertinents. Les resultats presentes dans ce resume ont ete presentes lors de la reunion annuelle de l’association americaine de la recherche contre le cancer (American Association for Cancer Research, AACR), qui a eu lieu du 1er au 5 avril 2017 a Washington, aux Etats-Unis, et publies dans le compte rendu de la conference comme resume CT075.

Introduction Dans le cadre de l’essai CheckMate 067, l’association de nivolumab (NIVO, anti-PD-1) et d’ipilimumab (IPI, anti-CTLA-4) a ameliore de maniere significative la survie sans progression mediane (SSPm) et le taux de reponse objective (TRG) par rapport a l’IPI seul chez des patients atteints de melanome avance. Nous rapportons les resultats d’efficacite et de securite d’emploi mis a jour de cette etude. Materiel et methodes Des patients naifs de traitement ( n = 945) ont recu de maniere randomisee selon un ratio 1 :1 :1 soit du NIVO 1 mg/kg toutes les 3 semaines + IPI 3 mg/kg toutes les 3 semaines × 4 (suivis de NIVO 3 mg/kg toutes les 2 semaines), soit du NIVO 3 mg/kg toutes les 2 semaines + placebo, soit de l’IPI 3 mg/kg toutes les 3 semaines × 4 + placebo, jusqu’a progression ou toxicite inacceptable. Les patients ont ete stratifies selon leur statut PD-L1, statut mutationnel BRAF et stade M. Les co-criteres d’evaluation principaux etaient la SSPm et la survie globale (les donnees restent precoces). Les criteres d’evaluation secondaires etaient l’efficacite selon le statut PD-L1 et la securite d’emploi. Resultats A ≥ 18 mois de suivi, la SSPm a continue d’etre nettement plus longue pour NIVO + IPI (11,5 mois) et NIVO (6,9 mois) que pour IPI (2,9 mois) ( p BRAF et etait de 11,3, 7,1 et 2,8 mois chez les patients avec BRAF de type sauvage, respectivement. La frequence et les types d’EI de grade 3/4 lies au traitement correspondaient aux donnees rapportees precedemment (NIVO + IPI : 56,5 % ; NIVO : 19,8 % ; IPI : 27,0 %). Conclusion NIVO + IPI et NIVO continuent de demontrer une activite clinique superieure a celle de l’IPI. L’association NIVO + IPI a engendre une SSP et un TRG plus importants numeriquement que NIVO seul, y compris chez les patients presentant une mutation BRAF . Reutilise avec la permission de l’ American Society of Clinical Oncology (ASCO, societe americaine d’oncologie clinique). Ce resume a ete accepte et presente a la reunion annuelle de l’ASCO 2016. Tous droits reserves.

Introduction Les resultats d’essais cliniques ont montre une amelioration significative du taux de reponse objective et de la survie sans progression (SSP) avec nivolumab (NIVO ; un anticorps anti-PD-1) plus ipilimumab (IPI ; un anticorps anti-CTLA-4) en comparaison avec IPI seul dans le melanome avance. Nous rapportons les premiers resultats de survie globale (SG) issus d’un essai clinique randomise evaluant l’association de traitements NIVO + IPI. Materiel et methodes Dans cet essai de phase II (CheckMate 069), 142 patients atteints de melanome avance et naif de traitement ont recu de maniere randomisee selon un ratio 2:1 (stratifiees par statut mutationnel BRAF) soit NIVO 1 mg/kg plus IPI 3 mg/kg, soit IPI 3 mg/kg plus placebo, toutes les 3 semaines pour 4 doses, suivis de NIVO 3 mg/kg ou placebo respectivement, toutes les deux semaines jusqu’a progression de la maladie ou toxicite inacceptable. Le critere d’evaluation principal etait le taux de reponse objective confirmee evaluee par l’investigateur parmi les patients atteints de melanome avec BRAF de type sauvage. Les criteres d’evaluation secondaires comprenaient la SSP chez les patients presentant des tumeurs avec BRAF de type sauvage et la securite d’emploi. La SG etait un critere d’evaluation exploratoire. La cloture de bases de donnees la plus recente a eu lieu le 29 fevrier 2016 (suivi minimum de 2 ans). Resultats Nous avons alloue de maniere randomisee 95 patients a NIVO + IPI et 47 a IPI (72 et 37 patients atteints de tumeurs avec BRAF V600 de type sauvage, respectivement). A 2 ans de suivi, le taux de SG chez les patients atteints de tumeurs avec BRAF de type sauvage etait de 69 % pour NIVO + IPI vs. 53 % pour IPI seul ; la SG mediane n’a pas ete atteinte dans le groupe NIVO + IPI et etait de 24,8 mois pour le groupe IPI (rapport de risque : 0,58 ; IC a 95 % : 0,31–1,08). Les taux de SSP a 2 ans etaient de 54 % pour NIVO + IPI vs. 11 % pour IPI seul ; la SSP n’a pas ete atteinte dans le groupe NIVO + IPI et etait de 4,4 mois pour le groupe IPI (rapport de risque : 0,35 ; IC a 95 % : 0,21–0,59 ; p Conclusion L’association de premiere ligne NIVO + IPI a conduit a un taux numeriquement plus eleve de SG a 2 ans que l’IPI seul en premiere ligne chez les patients atteints de melanome avance. Aucun nouveau probleme de securite d’emploi n’a ete observe apres un suivi prolonge. Ce resume a ete accepte a la 6 e reunion europeenne post-Chicago sur le melanome/cancer de la peau (Munich, Allemagne ; 30 juin–1 er juillet 2016).