Willenbacher, Wolfgang

Abstract Patients with relapsed/refractory (R/R) classical Hodgkin lymphoma (cHL) for whom autologous hematopoietic cell transplantation (auto-HCT) had failed experienced frequent and durable responses to nivolumab in the phase 2 CheckMate 205 trial. We present updated results (median follow-up, ∼5 years). Patients with R/R cHL who were brentuximab vedotin (BV)–naive (cohort A), received BV after auto-HCT (cohort B), or received BV before and/or after auto-HCT (cohort C) were administered with nivolumab 3 mg/kg IV every 2 weeks until progression or unacceptable toxicity. Patients in cohort C with complete remission (CR) for 1 year could discontinue nivolumab and resume upon relapse. Among 243 patients (cohort A, n = 63; B, n = 80; and C, n = 100), the objective response rate (ORR) was 71.2% (95% confidence interval [CI], 65.1-76.8); the CR rate was 21.4% (95% CI, 16.4-27.1). Median duration of response, CR, and partial remission were 18.2 (95% CI, 14.7-26.1), 30.3, and 13.5 months, respectively. Median progression-free survival was 15.1 months (95% CI, 11.3-18.5). Median overall survival (OS) was not reached; OS at 5 years was 71.4% (95% CI, 64.8-77.1). In cohort C, all 3 patients who discontinued in CR and were subsequently re-treated achieved objective response. No new or unexpected safety signals were identified. This 5-year follow-up of CheckMate 205 demonstrated favorable OS and confirmed efficacy and safety of nivolumab in R/R cHL after auto-HCT failure. Results suggest patients may discontinue treatment after persistent CR and reinitiate upon progression. This trial was registered at www.clinicaltrials.gov as #NCT02181713.

Abstract Introduction: Nivolumab (nivo), an immune checkpoint inhibitor targeting the programmed death-1 (PD-1) receptor, augments T-cell activation and restores antitumor T-cell function. In the phase 2 CheckMate 205 study (NCT02181738), nivo demonstrated frequent (65-73%) and durable objective responses across 3 cohorts of patients (pts) with relapsed/refractory (R/R) cHL after failure of autologous hematopoietic cell transplantation (Fanale M et al. ICML 2017 [oral 125]). While most pts with cHL are cured with first-line therapy, those with advanced-stage disease are more likely to relapse or progress. More aggressive regimens (eg, BEACOPPesc., Borchmann P et al. Lancet Oncol 2017) are associated with improved progression-free survival (PFS) but are hampered by excessive toxicities and have limited applicability in elderly pts.PD-1 ligand gene amplification has been linked to poorer outcomes in cHL pts treated with standard induction regimens (Roemer MG et al. J Clin Oncol 2016) but is associated with improved responses to nivo in R/R cHL (Younes A et al. Lancet Oncol 2016), suggesting that PD-1 blockade may benefit pts in the frontline setting. We therefore assessed the safety and efficacy of nivo as a single-agent lead-in treatment followed by nivo in combination with chemotherapy, excluding bleomycin due to potential overlapping pulmonary toxicity, for pts with previously untreated advanced-stage cHL. Methods: Cohort D of CheckMate 205 enrolled untreated pts (aged ≥18 y) with advanced-stage newly diagnosed cHL (stage III, IV, or II with B symptoms and extranodal or bulky disease) and ECOG score 0-1. Pts received 4 biweekly doses of nivo monotherapy (240 mg IV flat dose) followed by nivo plus chemotherapy (nivo 240 mg IV, doxorubicin, vinblastine, dacarbazine [N-AVD]) for 6 cycles (12 doses). The primary endpoint was safety and tolerability: proportion of pts with ≥1 grade (G) 3-5 treatment-related adverse event (TRAE) ≤30 d after last dose. Additional endpoints included rates of discontinuation and of independent radiologic review committee-assessed complete remission (CR). Results: At database lock (June 2017), 51 pts had been treated, with a median (range) follow-up of 8 (1-11) mo. Median (range) age was 37 (18-87) y; 29 (57%) pts had stage IV disease, and 41 (80%) had B symptoms. At baseline, 7 (14%) pts had bulky disease and 17 (33%) had extranodal involvement. International prognostic score was ≥3 in 25 (49%) pts. At analysis, 49 (96%) pts had completed nivo monotherapy treatment, receiving all 4 doses; 1 pt discontinued due to disease progression and 1 due to study drug toxicity (G1-2 hyperthyroidism), subsequently receiving AVD only. TRAEs for both treatment phases are shown in the Table. During nivo monotherapy, 2 pts had 1 dose delay each due to an AE; 2 (4%) pts had serious AEs (SAEs; 1 G1-2 hyperthyroidism; 1 G1-2 polyneuropathy); an immune-mediated AE (IMAE), G1-2 hyperthyroidism, was reported in 2 (4%) pts. Fifty pts started combination therapy; at database lock, 35 (70%) had completed therapy, with 34 (69%) receiving 12 N-AVD doses. With N-AVD, 10 (20%) pts had SAEs, 6 G3-4; the most common G3-4 SAE was febrile neutropenia in 2 (4%) pts; IMAEs occurring in >1 pt were hypothyroidism in 8 (16%) pts and increased ALT in 2 (4%). AEs leading to discontinuation of N-AVD occurred in 2 pts: G1-2 hepatic abnormality, and G3-4 febrile neutropenia (FN) and Klebsiella bacteremia. The pt who developed FN and Klebsiella bacteremia died 38 d after the first dose of his fifth cycle of N-AVD due to study drug toxicity of acute respiratory insufficiency. Important primary, secondary, and exploratory endpoints (including CR and objective response rates at end of monotherapy, after 2 combocycles and end of therapy, and PFS) will be presented at the meeting. Conclusions: Nivo monotherapy followed by N-AVD combination therapy was well-tolerated in pts with newly diagnosed, untreated, advanced-stage cHL. Nearly all pts completed nivo monotherapy treatment and started combination therapy with N-AVD. The safety profile was consistent with historical experience of nivo and AVD separately, with no new safety signals. Nivo followed by N-AVD may provide a tolerable alternative treatment option to standard-of-care multi-agent chemotherapy for pts with newly diagnosed advanced-stage cHL. Study support: BMS. Writing support: Matthew Thomas, PhD, Caudex, funded by BMS. Disclosures Ramchandren: Janssen: Research Funding; Pharmacyclics: Research Funding; Merck: Research Funding; Seattle Genetics: Consultancy. Fanale: CELGENE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC THERAPEUTICS: Research Funding; GENENTECH: Research Funding; MERCK: Membership on an entity's Board of Directors or advisory committees, Research Funding; MOLECULAR TEMPLATES: Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees; SEATTLE GENETICS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TAKEDA: Honoraria, Research Funding; ONYX: Research Funding. Rueda: Bristol-Myers Squibb: Consultancy. Armand: Roche: Research Funding; Genmab: Consultancy; Infinity: Consultancy; Sigma Tau: Research Funding; Tensha: Research Funding; Affimed: Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Otsuka: Research Funding; Pfizer: Consultancy, Research Funding; Merck & Co., Inc.: Consultancy, Research Funding; Sequenta/Adaptive: Research Funding. Trněný: Janssen: Consultancy, Honoraria; Roche: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Feldman: Pharmacyclics: Speakers Bureau; Celgene: Speakers Bureau; Bristol-Myers Squibb: Consultancy; Kite Pharma: Speakers Bureau; Seattle Genetics: Honoraria, Research Funding, Speakers Bureau; AbbVie: Speakers Bureau; Janssen: Speakers Bureau. Ansell: Merck: Research Funding; Seattle Genetics: Research Funding; Bristol-Myers Squibb: Research Funding; Celldex: Research Funding; Affimed: Research Funding. Jaeger: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses; Novartis Pharmaceuticals Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Accommodations, Expenses. Cohen: Bioinvent: Consultancy, Membership on an entity's Board of Directors or advisory committees; LAM Therapeutics, Inc: Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takada: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol Myers Squibb: Research Funding; Infinity: Consultancy, Membership on an entity's Board of Directors or advisory committees. Savage: Bristol-Myers Squibb: Honoraria; Seattle Genetics: Consultancy, Honoraria; Roche: Research Funding; Celgene: Consultancy; Merck: Honoraria. Willenbacher: Bristol-Myers Squibb: Consultancy, Honoraria. Sacchi: Bristol-Myers Squibb: Employment. Sumbul: Bristol-Myers Squibb: Employment.

7520 Background: We report results of a phase 2, open-label study of durvalumab (durva) in combination with R-CHOP or R2-CHOP (R-CHOP + lenalidomide) in previously untreated, high-risk diffuse large B-cell lymphoma (DLBCL). Methods: Subjects (≥18 y; ECOG 0–2) with previously untreated, high/high-intermediate risk DLBCL (IPI ≥3/NCCN-IPI ≥4) were stratified to durva + R-CHOP (Arm A, GCB DLBCL) or R2-CHOP for 6–8 cycles (Arm B, ABC DLBCL) based on cell of origin identified by gene expression followed by durva consolidation up to month 12 from start of induction. After FDA placed clinical holds on trials including combination therapy with checkpoint inhibitors and immunomodulatory agents, the study was revised to include both ABC and GCB in Arm A (durva + R-CHOP). The primary endpoint was complete response rate (CRR) at end of induction; secondary endpoints were rate of subjects continuing to consolidation, safety, and response in biological. Results: A total of 46 subjects were treated (safety; A/B, n=43/3); median age, 62/66 y; male, 61%/67%; ECOG 2, 19%/33%; Ann Arbor stage IV, 79%/33%; bulky disease: 49%/67%; double/triple-hit lymphoma, 30%/33%. As of Aug 2, 2018, 30/3 (A/B) had completed induction therapy, and 19 subjects (A) were ongoing. CRR (95% confidence interval) at end of induction was (A) 54% (37%-71%) and (B) 67% (9%-99%); 68%/67% (A/B) continued to consolidation therapy and were progression free at month 12. Safety profile was as expected for the components of the combination regimen with no new safety signal identified. Frequent treatment-emergent adverse events (TEAEs; ≥25%; A+B) included fatigue (61%), neutropenia (52%), peripheral sensory neuropathy (50%), nausea (46%), diarrhea (28%); constipation, decreased appetite, insomnia, pyrexia (24% each); and alopecia, dizziness, dyspnea, headache, stomatitis (22% each). Grade 3/4 TEAEs occurred in 84%/100% of subjects (A/B), and 3 subjects (2/1) died with no death related to study treatment. Follow-up for efficacy and safety is ongoing. Conclusions: Durva + R-CHOP combination therapy is safe and demonstrates encouraging response rates in subjects with high-risk DLBCL including double-hit lymphoma. Clinical trial information: NCT03003520.

8589 Background: Denosumab (dmab) is a fully human monoclonal antibody against RANKL and is superior to ZA in preventing skeletal-related events (SREs) as shown in 3 identically designed phase 3 trials (N=5723). Overall survival (OS) was balanced between treatment groups in the overall study populations of these trials. In the trial of patients (pts) with solid tumors (excluding breast and prostate) and multiple myeloma (MM), OS was longer for dmab pts with lung cancer, shorter for pts with MM, and balanced for pts with other solid tumors. This analysis further characterizes the results from the MM subset of this trial. Methods: Pts with solid tumors or MM were randomized (1:1) to receive 120 mg of SC dmab or 4 mg of IV ZA Q4W. Daily calcium and vit D supplements were strongly recommended. The primary endpoint was the time to first on-study SRE; results from the primary endpoint and lung cancer subset were previously reported. Results: Of 1776 randomized pts, 10% had MM (93 ZA, 87 dmab). OS favored ZA (hazard ratio: 2.26; 10 subject difference in deaths). 1-year OS was 83% dmab, 97% ZA. Imbalances in baseline prognostic characteristics were observed. More pts in the dmab arm had low baseline renal function (CrCl < 40 mL/min) (ZA 2 [2%], dmab 9 [10%]) and more ZA pts underwent stem cell transplant (ZA 23 [25%], dmab 15 [17%]). Additionally, more ZA pts had stage I tumors at diagnosis (ZA 13 [14%], dmab 9 [10%]) and better performance status (ECOG = 0; ZA 30 [32%], dmab 21 [24%]). Study discontinuations due to consent withdrawal or lost to follow-up were also higher in the ZA group (ZA 17 [18%], dmab 11 [13%]) and occurred earlier in the ZA arm (ZA 59%, dmab 45% within 9 months of randomization). Conclusions: In this SRE study of dmab vs ZA, pts were stratified by baseline characteristics known to affect SRE outcomes, but not by prognostic factors or concurrent anticancer therapy that may impact survival in MM. OS results in the MM cohort are difficult to interpret due to small sample size and imbalances in baseline disease characteristics, stem cell transplant therapy, and consent withdrawal or loss of follow-up that favored ZA. A phase 3 trial is currently underway, which controls for these factors in pts with MM. Clinical trial information: NCT00330759.

Background:Up to 30% of newly diagnosed patients (pts) with advanced‐stage classical Hodgkin lymphoma (cHL) are not cured by multi‐agent chemotherapy. High expression of the programmed death‐1 (PD‐1) ligands in these pts, associated with frequent genetic alterations at chromosome 9p24.1 in Hodgkin Reed‐Sternberg cells, supports the investigation of front‐line PD‐1 blockade in cHL (Roemer MG et al. J Clin Oncol 2016). Promising activity and acceptable safety was previously reported in newly diagnosed pts with advanced‐stage cHL treated with nivolumab, an anti–PD‐1 immune checkpoint inhibitor monoclonal antibody, followed by nivolumab plus doxorubicin, vinblastine and dacarbazine (N‐AVD) at a 9‐month follow‐up of Cohort D of the CheckMate 205 study (NCT02181738; Ramchandren R et al. EHA 2018).Aims:To further characterize the efficacy, including post hoc Deauville assessment, and safety of nivolumab followed by N‐AVD in pts with newly diagnosed advanced‐stage cHL with 2‐year extended follow‐up of CheckMate 205 Cohort D.Methods:Pts ≥ 18 years of age with newly diagnosed advanced‐stage cHL (stage IIB with unfavorable risk factors, III, or IV) received 4 doses of nivolumab monotherapy (240 mg IV every 2 weeks) followed by N‐AVD combination therapy for 6 cycles (12 doses). Primary endpoint was safety; secondary endpoints included complete remission (CR) rate per independent review committee (IRC) at end of study therapy (EOT) using 2007 International Working Group criteria. Complete metabolic response (CMR) was defined as a Deauville score of ≤ 3 (PET negative). Overall survival (OS) and modified progression‐free survival (PFS) were exploratory endpoints; PFS was assessed in a post hoc analysis.Results:Fifty‐one pts were treated (median age 37 years); minimum follow‐up was 24.4 months at data cutoff. Other baseline characteristics have been previously described (Ramchandren R et al. EHA 2018). Monotherapy was completed by 49/51 (96%) pts, combination therapy by 45/50 (90%); 48 pts entered follow‐up. After 2 combination cycles, CR rate was 51% per IRC (71% CMR) and 71% per investigator; at EOT, CR rate was 69% (75% CMR) per IRC and 80% per investigator. At 21 months, modified PFS rate per investigator was 80% (95% CI, 66–89) and PFS rate per investigator was 83% (95% CI, 69–91; Figure). Overall, 30 (59%) pts experienced grade 3–4 TRAEs, most commonly neutropenia in 21 (41%). The most common grade 3–4 immune‐mediated AE was hepatitis (2 pts, 4%). No grade 5 TRAEs occurred ≤ 30 days from last dose; 2 deaths were reported during the extended follow‐up: 1 pt (age 68 years) died 38 days after last dose due to study drug toxicity; another (age 85 years) died 451 days after last dose due to disease progression.Summary/Conclusion:With extended follow‐up, nivolumab followed by N‐AVD demonstrated a 21‐month PFS rate of 83% per investigator, a high metabolic response rate with 75% CMR at EOT per IRC, with no new safety signals. Incorporation of Deauville assessment improved the concordance of CR between IRC‐ and investigator‐assessed responses. Nivolumab followed by N‐AVD provides a promising alternative treatment option in newly diagnosed advanced‐stage cHL.image

PURPOSE Nivolumab, an anti–programmed death-1 monoclonal antibody, has demonstrated frequent and durable responses in relapsed/refractory classic Hodgkin lymphoma (cHL). We report results from Cohort D of the CheckMate 205 trial, which assessed nivolumab monotherapy followed by nivolumab plus doxorubicin, vinblastine, and dacarbazine (N-AVD) for newly diagnosed cHL. METHODS Patients 18 years of age or older with untreated, advanced-stage (defined as III to IV and IIB with unfavorable risk factors) cHL were eligible for Cohort D of this multicenter, noncomparative, phase II trial. Patients received nivolumab monotherapy for four doses, followed by 12 doses of N-AVD; all doses were every 2 weeks, and nivolumab was administered at 240 mg intravenously. The primary end point was safety. Efficacy end points included objective response rate and modified progression-free survival, defined as time to disease progression/relapse, death, or next therapy. Chromosome 9p24.1 alterations and programmed death-ligand 1 expression were assessed in Hodgkin Reed-Sternberg cells in evaluable patients. RESULTS A total of 51 patients were enrolled and treated. At diagnosis, 49% of patients had an International Prognostic Score of 3 or greater. Overall, 59% experienced a grade 3 to 4 treatment-related adverse event. Treatment-related febrile neutropenia was reported in 10% of patients. Endocrine immune-mediated adverse events were all grade 1 to 2 and did not require high-dose corticosteroids; all nonendocrine immune-mediated adverse events resolved (most commonly, rash; 5.9%). At the end of therapy, the objective response rate (95% CI) per independent radiology review committee was 84% (71% to 93%), with 67% (52% to 79%), achieving complete remission (five patients [10%] were nonevaluable and counted as nonresponders). With a minimum follow-up of 9.4 months, 9-month modified progression-free survival was 92%. Patients with higher-level Hodgkin Reed-Sternberg programmed death-ligand 1 expression had more favorable responses to N-AVD ( P = .041). CONCLUSION Nivolumab followed by N-AVD was associated with promising efficacy and safety profiles for newly diagnosed, advanced-stage cHL.