Benedetto Farsaci

Nivolumab for classical Hodgkin's lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin: a multicentre, multicohort, single-arm phase 2 trial

Background Malignant cells of classical Hodgkin lymphoma (cHL) are characterised by genetic alterations at the 9p24·1 locus. This leads to overexpression of the programmed death 1 (PD-1) ligands and enables tumour cells to evade immune surveillance. A phase 1b study showed that nivolumab, a PD-1-blocking antibody, produced a high response rate in patients with relapsed and refractory cHL, with an acceptable safety profile. This phase 2 study assessed the clinical benefit of nivolumab monotherapy in patients with cHL after autologous stem-cell transplantation and brentuximab vedotin failure. Methods This ongoing phase 2 study (NCT02181738) assessed the efficacy and safety of nivolumab, administered intravenously over 60 minutes at 3 mg/kg every 2 weeks, in adult patients with cHL who had failed both autologous stem-cell transplantation and brentuximab vedotin. The primary endpoint was objective response rate by independent radiologic review committee (IRRC) assessment. Secondary and other endpoints included duration of response, safety, and assessment of PD-L1 and PD-L2 loci and PD-L1 and PD-L2 protein expression. Findings Among 80 treated patients, the median number of prior therapies was four (range 3–15). With a mean (SD) follow-up of 8·6 months (2·02), objective response rate per IRRC was 66·3% (53/80). The most common drug-related adverse events (≥15%) included fatigue, infusion-related reaction, and rash. The most common drug-related grade 3–4 adverse events were neutropenia and increased lipase levels (both n=4). The most common serious adverse event (any grade) was pyrexia (n=3). Interpretation Nivolumab demonstrated a high response rate and an acceptable safety profile in patients with cHL who progressed following autologous stem-cell transplantation and brentuximab vedotin. Nivolumab may therefore provide a novel treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response. Funding Bristol-Myers Squibb.BACKGROUND Malignant cells of classical Hodgkins lymphoma are characterised by genetic alterations at the 9p24.1 locus, leading to overexpression of PD-1 ligands and evasion of immune surveillance. In a phase 1b study, nivolumab, a PD-1-blocking antibody, produced a high response in patients with relapsed and refractory classical Hodgkins lymphoma, with an acceptable safety profile. We aimed to assess the clinical benefit and safety of nivolumab monotherapy in patients with classical Hodgkins lymphoma after failure of both autologous stem-cell transplantation and brentuximab vedotin. METHODS In this ongoing, single-arm phase 2 study, adult patients (aged ≥18 years) with recurrent classical Hodgkins lymphoma who had failed to respond to autologous stem-cell transplantation and had either relapsed after or failed to respond to brentuximab vedotin, and with an Eastern Cooperative Oncology Group performance status score of 0 or 1, were enrolled from 34 hospitals and academic centres across Europe and North America. Patients were given nivolumab intravenously over 60 min at 3 mg/kg every 2 weeks until progression, death, unacceptable toxicity, or withdrawal from study. The primary endpoint was objective response following a prespecified minimum follow-up period of 6 months, assessed by an independent radiological review committee (IRRC). All patients who received at least one dose of nivolumab were included in the primary and safety analyses. This trial is registered with ClinicalTrials.gov, number NCT02181738. FINDINGS Among 80 treated patients recruited between Aug 26, 2014, and Feb 20, 2015, the median number of previous therapies was four (IQR 4-7). At a median follow-up of 8·9 months (IQR 7·8-9·9), 53 (66·3%, 95% CI 54·8-76·4) of 80 patients achieved an IRRC-assessed objective response. The most common drug-related adverse events (those that occurred in ≥15% of patients) included fatigue (20 [25%] patients), infusion-related reaction (16 [20%]), and rash (13 [16%]). The most common drug-related grade 3 or 4 adverse events were neutropenia (four [5%] patients) and increased lipase concentrations (four [5%]). The most common serious adverse event (any grade) was pyrexia (three [4%] patients). Three patients died during the study; none of these deaths were judged to be treatment related. INTERPRETATION Nivolumab resulted in frequent responses with an acceptable safety profile in patients with classical Hodgkins lymphoma who progressed after autologous stem-cell transplantation and brentuximab vedotin. Therefore, nivolumab might be a new treatment option for a patient population with a high unmet need. Ongoing follow-up will help to assess the durability of response. FUNDING Bristol-Myers Squibb.

Nivolumab for Relapsed/Refractory Classic Hodgkin Lymphoma After Failure of Autologous Hematopoietic Cell Transplantation: Extended Follow-Up of the Multicohort Single-Arm Phase II CheckMate 205 Trial

Purpose Genetic alterations causing overexpression of programmed death-1 ligands are near universal in classic Hodgkin lymphoma (cHL). Nivolumab, a programmed death-1 checkpoint inhibitor, demonstrated efficacy in relapsed/refractory cHL after autologous hematopoietic cell transplantation (auto-HCT) in initial analyses of one of three cohorts from the CheckMate 205 study of nivolumab for cHL. Here, we assess safety and efficacy after extended follow-up of all three cohorts. Methods This multicenter, single-arm, phase II study enrolled patients with relapsed/refractory cHL after auto-HCT treatment failure into cohorts by treatment history: brentuximab vedotin (BV)–naïve (cohort A), BV received after auto-HCT (cohort B), and BV received before and/or after auto-HCT (cohort C). All patients received nivolumab 3 mg/kg every 2 weeks until disease progression/unacceptable toxicity. The primary end point was objective response rate per independent radiology review committee. Results Overall, 243 patients were treated; 63 in cohort A, 80 in cohort B, and 100 in cohort C. After a median follow-up of 18 months, 40% continued to receive treatment. The objective response rate was 69% (95% CI, 63% to 75%) overall and 65% to 73% in each cohort. Overall, the median duration of response was 16.6 months (95% CI, 13.2 to 20.3 months), and median progression-free survival was 14.7 months (95% CI, 11.3 to 18.5 months). Of 70 patients treated past conventional disease progression, 61% of those evaluable had stable or further reduced target tumor burdens. The most common grade 3 to 4 drug-related adverse events were lipase increases (5%), neutropenia (3%), and ALT increases (3%). Twenty-nine deaths occurred; none were considered treatment related. Conclusion With extended follow-up, responses to nivolumab were frequent and durable. Nivolumab seems to be associated with a favorable safety profile and long-term benefits across a broad spectrum of patients with relapsed/refractory cHL.

Major Histocompatibility Complex Class II and Programmed Death Ligand 1 Expression Predict Outcome After Programmed Death 1 Blockade in Classic Hodgkin Lymphoma.

Purpose Hodgkin Reed-Sternberg (HRS) cells evade antitumor immunity by multiple means, including gains of 9p24.1/ CD274(PD-L1)/ PDCD1LG2(PD-L2) and perturbed antigen presentation. Programmed death 1 (PD-1) receptor blockade is active in classic Hodgkin lymphoma (cHL) despite reported deficiencies of major histocompatibility complex (MHC) class I expression on HRS cells. Herein, we assess bases of sensitivity to PD-1 blockade in patients with relapsed/refractory cHL who were treated with nivolumab (anti-PD-1) in the CheckMate 205 trial. Methods HRS cells from archival tumor biopsies were evaluated for 9p24.1 alterations by fluorescence in situ hybridization and for expression of PD ligand 1 (PD-L1) and the antigen presentation pathway components-β2-microglobulin, MHC class I, and MHC class II-by immunohistochemistry. These parameters were correlated with clinical responses and progression-free survival (PFS) after PD-1 blockade. Results Patients with higher-level 9p24.1 copy gain and increased PD-L1 expression on HRS cells had superior PFS. HRS cell expression of β2-microglobulin/MHC class I was not predictive for complete remission or PFS after nivolumab therapy. In contrast, HRS cell expression of MHC class II was predictive for complete remission. In patients with a > 12-month interval between myeloablative autologous stem-cell transplantation and nivolumab therapy, HRS cell expression of MHC class II was associated with prolonged PFS. Conclusion Genetically driven PD-L1 expression and MHC class II positivity on HRS cells are potential predictors of favorable outcome after PD-1 blockade. In cHL, clinical responses to nivolumab were not dependent on HRS cell expression of MHC class I.

Abstract LB-072: Impact of baseline serum cytokines on survival in patients (pts) with advanced squamous (SQ) non-small cell lung cancer (NSCLC) treated with nivolumab (nivo) or docetaxel (doc): Exploratory analyses from CheckMate 063 and CheckMate 017

Background: Nivo, a fully human IgG4 programmed death-1 (PD-1) immune checkpoint inhibitor antibody, is approved in the United States and European Union for the treatment of pts with advanced SQ NSCLC refractory to prior chemotherapy, based on results of phase 2 (CheckMate 063) and phase 3 (CheckMate 017) trials. In these studies, PD-1 ligand (PD-L1) expression was neither predictive nor prognostic of survival benefit. Here we present results of exploratory analyses from these studies evaluating the potential correlation of baseline serum cytokines with overall survival (OS) in pts with SQ NSCLC. Methods: Baseline serum cytokine concentrations in evaluable pts from CheckMate 063 and CheckMate 017 treated with nivo (n = 222) or doc (n = 118) were analyzed using a custom HumanMAP quantitative multiplexed immunoassay (Myriad RBM, Austin, TX). Multivariate analyses using a stepwise variable selection were performed in a Cox model using a 6:4 training:test validation in nivo-treated subjects. The performance of the association with OS of the identified cytokine set in nivo-treated subjects was tested using time-varying receiver-operating characteristic (ROC) analysis. SQ-cytoscore, generated to quantify the effect of the identified cytokine set on OS, was computed as follows: 1) calculation of the tertile bin distribution of each cytokine in the set in all pts and assignment of a point score (0, 1, or 2) for each tertile expression of each cytokine; 2) calculation of SQ-cytoscore for each pt as the sum of points; 3) categorization of pts as SQ-cytoscore “high” or “low” based on the median cutoff. OS was analyzed in pts with high vs low SQ-cytoscore treated with nivo and doc using the Kaplan-Meier method and 18-mo data cutoffs for CheckMate 063 (June 2015) and CheckMate 017 (August 2015). Results: Of 26 evaluable baseline cytokines, a set of 14 was identified to be associated with OS. Median OS was longer in pts with high vs low SQ-cytoscore in both nivo- and doc-treated cohorts (nivo [n = 102 vs 120]: 15.6 vs 5.3 months, HR:0.48, 95%CI:0.36-0.64, P Conclusion: In pts with advanced SQ NSCLC pooled from 2 clinical trials, a set of serum cytokines (details to be presented) potentially associated with OS benefit was identified. The benefit of a high SQ-cytoscore appeared more profound in pts treated with nivo vs doc. These preliminary findings require prospective validation in future studies. Citation Format: Benedetto Farsaci, William J. Geese, Kaushal D. Desai, Chelsea Jin, Scott J. Antonia, Herve Lena, Leora Horn, David Planchard, Karen L. Reckamp, Thomas E. Stinchcombe, Scott Gettinger, Hossein Borghaei, Matthew D. Hellmann, Christopher Harbison, Dong Xu, M. Anne Blackwood-Chirchir, Naiyer Rizvi. Impact of baseline serum cytokines on survival in patients (pts) with advanced squamous (SQ) non-small cell lung cancer (NSCLC) treated with nivolumab (nivo) or docetaxel (doc): Exploratory analyses from CheckMate 063 and CheckMate 017. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr LB-072.