All-grade Adverse Events Research Articles

First-line (1L) ribociclib (RIB) plus letrozole (LET) for postmenopausal women with hormone receptor-positive (HR+), HER2- advanced breast cancer (ABC): MONALEESA-2 long-term safety results.

1078 Background: In the phase III MONALEESA-2 study (NCT01958021), 1L treatment (Tx) with RIB (cyclin-dependent kinase 4/6 inhibitor) plus LET significantly prolonged PFS vs placebo (PBO) + LET in patients (pts) with HR+/HER2– ABC (HR 0.56; P<0.0001). In the primary publication (data cutoff, Jan 2016), the median duration of exposure was 13.0 mo (RIB + LET) and 12.4 mo (PBO + LET), and the most common all-grade adverse events (AEs) in the RIB + LET arm were neutropenia (74.3%), nausea (51.5%), infections (50.3%), fatigue (36.5%), and diarrhea (35.0%; Hortobagyi GN, et al. N Engl J Med. 2016;375:1738-48). Here we present long-term safety data from MONALEESA-2. Methods: Pts received either RIB + LET (n=334) or PBO + LET (n=330). AEs were graded per CTCAE v4.03. Results: As of data cutoff (Oct 2018), 79 (24%) pts (RIB + LET) and 39 (12%) pts (PBO + LET) remained on Tx. The median duration of exposure was 20.2 mo (range, 0-54) for RIB + LET and 14.1 mo for PBO + LET, and 30% and 17%, respectively, had ≥ 36 mo of exposure. Neutropenia was the most common exposure-adjusted any-grade AE of special interest (AESI) in the RIB + LET arm (Table). AEs were the most common reason for RIB dose reductions (56.6%) and interruptions (73.4%). Discontinuations due to AEs occurred in 19.2% and 4.2% of pts in the RIB + LET and PBO + LET arms, respectively, and the most common AEs leading to discontinuation in the RIB + LET arm were increased ALT (4.5%), GI disorders (3.3%), and increased AST (2.7%). Prolonged QT led to dose interruption in 0.9% of patients (no discontinuations), and the additional follow-up did not reveal any sudden deaths related to prolonged QT interval beyond the 1 identified in the primary analysis. Conclusions: AEs occurring with 1L RIB + LET in postmenopausal pts with HR+/HER2– ABC were manageable and the safety profile was comparable to that in the primary report. Clinical trial information: NCT01958021. [Table: see text]

Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).

e20558 Background: Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers among which the metastatic disease represents ~ 57%, and long-term prognosis remains poor. Combined chemoimmunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through January 31, 2019. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (grade 3). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to significant heterogeneity among studies. Results: Nine phase 2 & 3 RCTs (Keynote – 021,189, 407, IMpower – 130, 131, 132, 150, checkmate-227, and Govindan et al) including 5042 patients with advanced NSCLC patients were included in the meta-analysis. The study arm used standard chemotherapy regimens in combination with ipilimumab, pembrolizumab, atezolizumab, or nivolumab while control arm used only standard chemotherapy regimens. The pooled HR for PFS was 0.65 (95% CI: 0.57-0.73; P = 0.00001), the pooled HR for OS was 0.72 (95% CI: 0.61-0.86; P = 0.0003), and the pooled RR for ORR was 1.45 (95 CI: 1.23-1.72; P = 0.0001). The pooled RRs for all-grade AEs and high-grade AEs were 1.03 (95% CI: 0.99-1.07; P = 0.13) and 1.21 (95% CI: 1.1-1.34; P = 0.0001), respectively. Conclusions: The combined chemoimmunotherapy can significantly improve PFS, OS, and ORR compared to standard chemotherapy for the first-line treatment of advanced NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.

Mutant IDH1 inhibitor ivosidenib (IVO; AG-120) in combination with azacitidine (AZA) for newly diagnosed acute myeloid leukemia (ND AML).

7011 Background: IVO, a mutant IDH1 (mIDH1) inhibitor, is approved for the treatment of relapsed/refractory mIDH1 AML. We report results from an ongoing phase 1b study of patients (pts) with mIDH1 ND AML ineligible for intensive treatment who received combination IVO+AZA (NCT02677922). Methods: Pts received oral IVO 500 mg daily continuously and subcutaneous AZA 75 mg/m2 on D1–7 in 28-d cycles. ORR comprised CR + CRi/CRp + PR+ MLFS. CR with partial hematologic recovery (CRh) was defined as CR with ANC > 0.5×109/L and platelets > 50×109/L. Exploratory analysis included digital PCR assessment of m IDH1 allele frequency in bone marrow mononuclear cells (≤0.04% sensitivity). Results: As of 9Oct2018, 23 pts received IVO+AZA (11 male; median age 76 yrs [range 61–88]). Median duration of exposure was 11 mo (0.3–25.3); 12 pts remained on treatment at data cutoff. All-grade adverse events (AEs) regardless of cause in ≥30% pts were thrombocytopenia (65%), nausea (61%), diarrhea (57%), anemia (52%), constipation (52%), febrile neutropenia (39%), pyrexia (39%), vomiting (35%), fatigue (35%), hypokalemia (35%), dizziness (35%), insomnia (35%), and neutropenia (30%). AEs of special interest included ECG QT prolonged (26%), IDH differentiation syndrome (17%), and leukocytosis (13%). Grade 3/4 AEs in ≥10% pts were thrombocytopenia (61%), anemia (44%), febrile neutropenia (39%), neutropenia (26%), sepsis (22%), and ECG QT prolonged (13%). ORR was 78% (n = 18): CR 57%, CRi/CRp 13%, and MLFS 9%. CR+CRh rate was 70% (n = 16). Median time to response was 1.8 mo (0.7–3.8) and to CR 3.5 mo (0.8–6.0); median response duration not yet reached. m IDH1 clearance was seen in 10/16 pts (63%) with CR/CRh, including 9/13 (69%) with CR. Conclusions: IVO+AZA was well tolerated with a safety profile consistent with IVO or AZA monotherapy. All-grade cytopenia-related AEs were infrequent relative to other non-intensive therapies. CR and ORR rates exceeded those of AZA alone (Dombret et al., Blood 2015) and most responders achieved m IDH1 mutation clearance. Based on these findings, a phase 3 double-blind placebo-controlled study of IVO +AZA (AGILE, NCT03173248) is actively enrolling pts. Clinical trial information: NCT02677922.

Results of the phase 1b study of ABBV-399 (telisotuzumab vedotin; teliso-v) in combination with erlotinib in patients with c-Met+ non-small cell lung cancer by EGFR mutation status.

3011 Background: Telisotuzumab vedotin (ABBV-399; teliso-v [T]) is a c-Met–targeted antibody and MMAE drug conjugate. Activity of T was shown in late-line c-Met+ non-small cell lung cancer (NSCLC) irrespective of EGFR mutation (M+) status. We present mature data from the T+ erlotinib (E) cohort of a phase 1b study (NCT02099058) by EGFR M+ status. Methods: T was administered at 2.4 mg/kg (dose-escalation phase) or 2.7 mg/kg IV Q3W, and E at 150 mg PO QD/prior tolerated dose in adult patients (pts) with advanced NSCLC. Efficacy-evaluable pts were c-Met+ (central lab IHC H-score ≥150 or local lab MET amplification/Ex 14 skipping) and had ≥1 postbaseline scan or discontinued study. EGFR M+ was defined as del19 or L858R by local lab. PK was assessed. Results: As of Dec 2018, 42 NSCLC pts received T+E; 37 were c-MET+ (36 evaluable; 35 H-score≥150, 1 MET amplified). Median age was 65 years, 25 pts (69%) had ECOG PS 1, 29 (81%) were EGFR M+ (97% had prior EGFR TKI, 55% 3rd-generation TKI, 69% TKI as last prior therapy, and 62% platinum doublet). All-grade (Gr; ≥20%) adverse events (AEs) were dermatitis acneiform (38%), diarrhea (36%), peripheral motor/sensory neuropathy (52%; 7% Gr 3), dyspnea, fatigue, hypoalbuminemia (31% each), decreased appetite, nausea (24% each), asthenia, vomiting (21% each). Gr ≥3 (≥10%) AE: pulmonary embolism (14%). PK of T+E was similar to single-agent T. The table presents efficacy data. Conclusions: These data suggest acceptable safety and promising activity of T+E and support further study in EGFR M+ c-Met+ NSCLC pts for whom frontline EGFR TKI failed. Clinical trial information: NCT02099058. [Table: see text]

A phase Ib trial of the cyclin-dependent kinase inhibitor dinaciclib (dina) in combination with pembrolizumab (P) in patients with advanced triple-negative breast cancer (TNBC).

1072 Background: Increased expression of the MYC transcriptional oncogene is found in 70% of TNBC and is associated with poor prognosis. In MYC-overexpressing TN xenografts, CDK1 inhibition with dina results in synthetic lethality, and attenuates distant metastasis. In syngeneic models, the combination of dina with anti-PD1 therapy is synergistic and increases immune cell tumor infiltration and activation. Methods: Patients (pts) with advanced TNBC were enrolled. Pts received intravenous dina day 1 and 8 in combination with fixed dose P 200 mg once every 21 days. Dina was dose escalated using a toxicity probability interval design targeting a dose limiting toxicity (DLT) rate of 25%. Evaluable disease and pre-treatment metastatic biopsies were required. After 17 pts were enrolled, eligibility was amended to require ≤2 lines of prior chemotherapy, and LDH ≤1.5x normal. Results: 22 pts were enrolled (median age 50, median 2 prior lines of therapy, 10 pts (45%) had disease which was previously ER+). Dina was dose escalated from 12 to 33 mg/m2 in 4 cohorts. No DLTs were observed. Of the first 5 patients in the 33 mg/m2 cohort, 2 pts required a dose reduction (1 pt due to recurrent grade (G) 3 fever and G2 chills; 1 pt due to recurrent G2 diarrhea, chills, fatigue), and 1 pt discontinued due to G3 hemolytic anemia. 4 additional pts were treated at 33 mg/m2 without DLT or dose reduction. G ≥3 adverse events (AEs) in all pts included neutropenia (ntp) (36.3%), febrile ntp (13.6%), and fatigue (13.6%). Most common all-grade AEs included fatigue (73%), diarrhea (59%), nausea (50%), ntp (45%), mucositis (32%), anorexia (23%). Immune-related AEs included sinusitis (3 pts), hemolytic anemia (1 pt), pneumonitis (1pt), and rash (2 pts). Of 21 pts evaluable for response, 1 pt had complete response (4.8%), 2 pts had partial response (9.5%), and 5 pts had stable disease (23.8%). Dose expansion and correlative biomarker studies are ongoing. Conclusions: The recommended phase 2 dose of dinaciclib given in combination with pembrolizumab is 33 mg/m2 on D1, 8 of 21-day cycle. Toxicities are generally manageable with dose reduction and dose delay. Clinical trial information: NCT01676753.

Comparative safety analysis of immunotherapy combined with chemotherapy versus monotherapy in solid tumors: a meta-analysis of randomized clinical trials.

Background: Combination treatment (chemotherapy plus immune checkpoint blockade [ICB]) has shown promising activity in terms of efficacy, but it has been suggested that its toxicity profile is less favorable compared to monotherapy.Methods: We conducted a meta-analysis of published randomized clinical trials comparing combination treatment to monotherapy (chemotherapy or ICB) in patients with metastatic solid tumors. Differences in rates of safety issues (all-grade adverse events, grade 3/4 adverse events, treatment-related deaths, treatment discontinuations) between groups were estimated. Subgroup analyses for the control group (chemotherapy or ICB as monotherapy) and immune checkpoint inhibitor (anti-CTLA-4 or anti-PD-1/PD-L1 antibodies) were performed.Results: A total of 4379 patients (ten studies) were included (monotherapy: 2026 patients; combination treatment: 2353 patients). Combination treatment presented more grade 3/4 adverse events (RR 1.32, 95% CI 1.12–1.55) and discontinuations (RR 2.31, 95% CI 1.28–4.16). There were no differences in the mortality rate between groups. Subgroup analyses showed a potentially more toxic profile with anti-CTLA-4 agents.Conclusions: Combination treatment is associated with an increase in grade 3/4 adverse events and treatment discontinuations compared to monotherapy, but not increased mortality. The toxicity profile of combination therapy should be considered with regard to the overlapping safety profiles.

Atezolizumab plus bevacizumab versus sunitinib in patients with previously untreated metastatic renal cell carcinoma (IMmotion151): a multicentre, open-label, phase 3, randomised controlled trial

A phase 2 trial showed improved progression-free survival for atezolizumab plus bevacizumab versus sunitinib in patients with metastatic renal cell carcinoma who express programmed death-ligand 1 (PD-L1). Here, we report results of IMmotion151, a phase 3 trial comparing atezolizumab plus bevacizumab versus sunitinib in first-line metastatic renal cell carcinoma. In this multicentre, open-label, phase 3, randomised controlled trial, patients with a component of clear cell or sarcomatoid histology and who were previously untreated, were recruited from 152 academic medical centres and community oncology practices in 21 countries, mainly in Europe, North America, and the Asia-Pacific region, and were randomly assigned 1:1 to either atezolizumab 1200 mg plus bevacizumab 15 mg/kg intravenously once every 3 weeks or sunitinib 50 mg orally once daily for 4 weeks on, 2 weeks off. A permuted-block randomisation (block size of 4) was applied to obtain a balanced assignment to each treatment group with respect to the stratification factors. Study investigators and participants were not masked to treatment allocation. Patients, investigators, independent radiology committee members, and the sponsor were masked to PD-L1 expression status. Co-primary endpoints were investigator-assessed progression-free survival in the PD-L1 positive population and overall survival in the intention-to-treat (ITT) population. This trial is registered with ClinicalTrials.gov, number NCT02420821. Of 915 patients enrolled between May 20, 2015, and Oct 12, 2016, 454 were randomly assigned to the atezolizumab plus bevacizumab group and 461 to the sunitinib group. 362 (40%) of 915 patients had PD-L1 positive disease. Median follow-up was 15 months at the primary progression-free survival analysis and 24 months at the overall survival interim analysis. In the PD-L1 positive population, the median progression-free survival was 11·2 months in the atezolizumab plus bevacizumab group versus 7·7 months in the sunitinib group (hazard ratio [HR] 0·74 [95% CI 0·57-0·96]; p=0·0217). In the ITT population, median overall survival had an HR of 0·93 (0·76-1·14) and the results did not cross the significance boundary at the interim analysis. 182 (40%) of 451 patients in the atezolizumab plus bevacizumab group and 240 (54%) of 446 patients in the sunitinib group had treatment-related grade 3-4 adverse events: 24 (5%) in the atezolizumab plus bevacizumab group and 37 (8%) in the sunitinib group had treatment-related all-grade adverse events, which led to treatment-regimen discontinuation. Atezolizumab plus bevacizumab prolonged progression-free survival versus sunitinib in patients with metastatic renal cell carcinoma and showed a favourable safety profile. Longer-term follow-up is necessary to establish whether a survival benefit will emerge. These study results support atezolizumab plus bevacizumab as a first-line treatment option for selected patients with advanced renal cell carcinoma. F Hoffmann-La Roche Ltd and Genentech Inc.

PCN174 ADVERSE EVENTS ASSOCIATED WITH IMMUNOTHERAPIES USED IN THE TREATMENT OF STAGE 3 AND 4 MELANOMA

Immunotherapy and targeted therapy have become standard treatments for patients with stage 3 and 4 melanoma. Despite their efficacy, both are associated with adverse events (AEs), which may be costly to manage. Data published on AEs associated with immunotherapies have not been reviewed in a targeted way over the past five years. This study aimed to identify the most frequently reported AEs associated with immunotherapies in the treatment of stage 3 and 4 melanoma. Targeted searches were conducted in the PubMed literature database to identify phase 3 studies reporting AEs associated with immunotherapies used in the treatment of stage 3 and 4 melanoma published in the past five years (January 1, 2014 to December 31, 2018). Study titles and abstracts were screened by two independent reviewers. Study design details and data on AEs by immunotherapy were extracted. AEs occurring in ≥10% of patients in any study group were recorded, in addition to grade ≥3 AEs occurring in ≥1% of patients. Twelve phase 3 studies reporting AEs associated with immunotherapies used in the treatment of stage 3 and 4 melanoma were included; all categorized AEs by grade (e.g., all, 1-2, ≥3). The following treatments were considered: ipilimumab, nivolumab, pembrolizumab, talimogene laherparepvec (T-VEC), and nivolumab plus ipilimumab. The most frequently reported AEs across all grades were fatigue, diarrhea, pruritus, rash, and nausea. Diarrhea, colitis, and fatigue were the most frequently reported grade ≥3 AEs. Certain all-grade AEs were associated with particular immunotherapies: fatigue with T-VEC (50-51% of patients), pruritis with ipilimumab (25-36% of patients), and diarrhea with nivolumab plus ipilimumab (44-45% of patients). Data from the last five years show that immunotherapies used in the treatment of stage 3 and 4 melanoma are associated with high rates of AEs. There is still substantial unmet need for therapies with improved safety profiles.

Treatment-Related Adverse Events of PD-1 and PD-L1 Inhibitors in Clinical Trials

Programmed cell death (PD-1) and programmed cell death ligand 1 (PD-L1) inhibitors have been increasingly used in cancer therapy. Understanding the treatment-related adverse events of these drugs is critical for clinical practice. To evaluate the incidences of treatment-related adverse events of PD-1 and PD-L1 inhibitors and the differences between different drugs and cancer types. PubMed, Web of Science, Embase, and Scopus were searched from October 1, 2017, through December 15, 2018. Published clinical trials on single-agent PD-1 and PD-L1 inhibitors with tabulated data on treatment-related adverse events were included. Trial name, phase, cancer type, PD-1 and PD-L1 inhibitor used, dose escalation, dosing schedule, number of patients, number of all adverse events, and criteria for adverse event reporting data were extracted from each included study, and bayesian multilevel regression models were applied for data analysis. Incidences of treatment-related adverse events and differences between different drugs and cancer types. This systematic review and meta-analysis included 125 clinical trials involving 20 128 patients; 12 277 (66.0%) of 18 610 patients from 106 studies developed at least 1 adverse event of any grade (severity), and 2627 (14.0%) of 18 715 patients from 110 studies developed at least 1 adverse event of grade 3 or higher severity. The most common all-grade adverse events were fatigue (18.26%; 95% CI, 16.49%-20.11%), pruritus (10.61%; 95% CI, 9.46%-11.83%), and diarrhea (9.47%; 95% CI, 8.43%-10.58%). The most common grade 3 or higher adverse events were fatigue (0.89%; 95% CI, 0.69%-1.14%), anemia (0.78%; 95% CI, 0.59%-1.02%), and aspartate aminotransferase increase (0.75%; 95% CI, 0.56%-0.99%). Hypothyroidism (6.07%; 95% CI, 5.35%-6.85%) and hyperthyroidism (2.82%; 95% CI, 2.40%-3.29%) were the most frequent all-grade endocrine immune-related adverse events. Nivolumab was associated with higher mean incidences of all-grade adverse events compared with pembrolizumab (odds ratio [OR], 1.28; 95% CI, 0.97-1.79) and grade 3 or higher adverse events (OR, 1.30; 95% CI, 0.89-2.00). PD-1 inhibitors were associated with a higher mean incidence of grade 3 or higher adverse events compared with PD-L1 inhibitors (OR, 1.58; 95% CI, 1.00-2.54). Different PD-1 and PD-L1 inhibitors appear to have varying treatment-related adverse events; a comprehensive summary of the incidences of treatment-related adverse events in clinical trials provides an important guide for clinicians.

Safety and efficacy profile of cyclin-dependent kinases 4/6 inhibitor palbociclib in cancer therapy: A meta-analysis of clinical trials.

BackgroundPalbociclib is a small‐molecule, cyclin‐dependent kinase 4 and 6 inhibitor, which prevents phosphorylation of the retinoblastoma (Rb) protein and inhibits cell‐cycle progression from G1 to S phase. We performed this meta‐analysis to estimate the safety and efficacy of palbociclib in cancer patients from clinical trials.MethodsPubMed and EMBASE were searched for eligible studies. Adverse events (AE) of grade ≥3 and all‐grade (1‐5) were extracted to calculate event rates. Odds ratios (ORs) with 95% confidence interval (CI) were calculated to estimate the safety of palbociclib in endocrine treatment‐combined studies. A fixed effects model was used when homogeneity was low (I 2 ≤ 50%). A random effects model was adopted when there was a significant heterogeneity (I 2 > 50%). For efficacy endpoints, hazard ratio (HR) and 95% CI for progression‐free survival (PFS) or overall survival (OS) were extracted and analyzed.ResultsNine clinical trials representing 1534 patients were identified. The most frequently observed all‐grade adverse events (AEs) in patients treated with palbociclib were neutropenia (event rate: 68.1%), leukopenia (51.7%), fatigue (35.9%), anemia (34.7%), and thrombocytopenia (30.9%). The most common grade 3 or more toxicities were neutropenia (51.6%), leukopenia (29.4%), and thrombocytopenia (7.5%). Hematologic adverse events had high occurrence in the palbociclib group. The pooled analysis of survival outcomes suggested that palbociclib produced clinical benefits in breast cancers and Rb‐positive tumors. More specifically, palbociclib was associated with significant improvement of PFS (HR: 0.518, 95% CI: 0.444‐0.604) in the treatment of ER‐positive and HER2‐negative breast cancer.ConclusionsHematologic adverse events were common in palbociclib‐treated cancer patients. Since palbociclib produced a higher PFS rate with a low serious complication rate, it can be a promising novel target therapy drug for treating ER‐positive and HER2‐negative breast cancer.

Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced squamous non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).

121 Background: Squamous Non-small cell lung cancer (NSCLC) accounts for ~30% of lung cancers, and long-term survival remains poor for advanced disease. Combined chemo-immunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced squamous NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥grade 3). Heterogeneity was assessed with Cochrane Q -statistic. Random effects were used due to significant heterogeneity among studies. Results: Three phase 3 RCTs (Keynote – 407, IMpower – 131, and Govindan et al) including 1991 patients with advanced squamous NSCLC patients were included in the meta-analysis. The study arm used standard chemotherapy regimens in combination with ipilimumab, pembrolizumab, or atezolizumab, while control arm used only standard chemotherapy regimens. The pooled HR for PFS was 0.71 (95% CI: 0.56-0.9; P = 0.005), the pooled HR for OS was 0.84 (95% CI: 0.68-1.04; P = 0.11), and the pooled RR for ORR was 1.19 (95 CI: 0.9-1.56; P = 0.22). The pooled RRs for all-grade AEs and high-grade AEs were 1.17 (95% CI: 0.99-1.39; P = 0.07) and 1.36 (95% CI: 1.19-1.56; P = 0.0001), respectively. Conclusions: The combined chemo-immunotherapy improves PFS without significant improvement in OS & ORR compared to standard chemotherapy for the first-line treatment of advanced squamous NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.

Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).

117 Background: Non-small cell lung cancer (NSCLC) accounts for ~85% of lung cancers among which the metastatic disease represents ~ 57%, and long-term prognosis remains poor. Combined chemo-immunotherapy can have synergistic anticancer activities through the immunomodulatory impact of checkpoint inhibitors and the immunogenic effect of chemotherapy. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line chemotherapy +/- immunotherapy in patients with advanced NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥ grade 3). Heterogeneity was assessed with Cochrane Q-statistic. Random effects were used due to significant heterogeneity among studies. Results: Seven phase 2 & 3 RCTs (Keynote-021,189, 407, IMpower-131, 150, checkmate-227, and Govindan et al) including 3785 patients with advanced NSCLC were included in the analysis. IMpower 150 trial allowed EGFR or ALK mutated patients. The study arm used standard treatment regimens in combination with ipilimumab, pembrolizumab, atezolizumab, or nivolumab, while control arm used only standard treatment regimens. The pooled HR for PFS was 0.65 (95% CI: 0.56-0.77; P=0.00001), the pooled HR for OS was 0.73 (95% CI: 0.59-0.90; P=0.003), and the pooled RR for ORR was 1.45 (95 CI: 1.17-1.8; P=0.0007). The pooled RRs for all-grade AEs and high-grade AEs were 1.1 (95% CI: 1-1.21; P=0.05) and 1.28 (95% CI: 1.13-1.46; P=0.0001), respectively. Conclusions: Adding immunotherapy to standard regimen significantly improves PFS, OS, and ORR for the first-line treatment of advanced NSCLC. The combined regimen results in a slightly higher risk of high-grade AEs without a significant increase in the risk of all-grade AEs.

Checkpoint inhibitors in combination with chemotherapy for first-line treatment of advanced nonsquamous non-small cell lung cancer: A systematic review and meta-analysis of randomized controlled trials (RCTs).

125 Background: RCTs have tested the role of adding immunotherapy to standard therapy in patients with advanced non-squamous non-small cell lung cancer (NSCLC) in the first-line setting. We conducted a systematic review and meta-analysis of RCTs to assess the efficacy and toxicity of adding immunotherapy in this patient population. Methods: We systematically conducted a comprehensive literature search using PUBMED, EMBASE and SCOPUS databases through October 1, 2018. RCTs of first-line standard therapy +/- immunotherapy in patients with advanced non-squamous NSCLC were incorporated in the analysis. A generic inverse variance method was used to calculate the estimated pooled Hazard ratio (HR) for overall survival (OS) and progression-free survival (PFS). The mantel-haenszel method was used to calculate the estimated pooled risk ratio (RR) with 95% confidence interval (CI) for pooled overall response rate (ORR), all-grade adverse events (AEs), and high-grade AEs (≥grade 3). Heterogeneity was assessed with Cochrane Q-statistic. Random effects were used due to significant heterogeneity among studies. Results: Three phase 2 & 3 RCTs (Keynote – 021,189 and IMpower – 150) including 1431 patients with advanced non-squamous NSCLC patients were included in the analysis. Keynote 021 & 189 trials did not allow patients with EGFR or ALK mutations, while IMpower 150 trial allowed EGFR or ALK mutations. The study arm used standard regimens in combination with pembrolizumab or atezolizumab while control arm used only standard regimens. The pooled HR for PFS was 0.57 (95% CI: 0.5-0.65; P=0.00001), the pooled HR for OS was 0.61 (95% CI: 0.43-0.87; P=0.006), and the pooled RR for ORR was 1.83 (95 CI: 1.13-2.95; P=0.01). The pooled RRs for all-grade AEs and high-grade AEs were 1 (95% CI: 0.99-1.02; P=0.48) and 1.11 (95% CI: 0.97-1.28; P=0.14), respectively. Conclusions: Pooled data showed significant improvement in PFS, OS & ORR with chemo-immunotherapy compared to the standard treatment regimen for the first-line treatment of advanced non-squamous NSCLC. There was no increase in the risk of all-grade and high-grade AEs.

Abstract P6-18-16: Ribociclib (RIBO) + letrozole (LET) in older patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC): Preliminary subgroup results from the phase 3b CompLEEment-1 trial

Abstract Background: The cyclin-dependent kinase (CDK)4/6 inhibitor RIBO is approved in combination with an aromatase inhibitor (AI) for HR+, HER2– ABC in postmenopausal women with no prior therapy for ABC, based on the MONALEESA-2 trial (Hortobagyi et al. NEJM 2016). Although a high proportion of patients with HR+, HER2– ABC are >65 years of age, older patients are often under-represented in clinical trials. Furthermore, treatment decisions may be complicated by comorbidities, functional status, and concurrent medications. Here, we report early safety results for patients ≥65 years of age enrolled in CompLEEment-1, an open-label, phase 3b trial evaluating RIBO+LET as first-line endocrine-based therapy in an expanded patient population. Methods: Patients with HR+, HER2– ABC, ≤1 line of prior chemotherapy (CT), and no prior endocrine therapy for ABC received RIBO (600 mg/day, 3 weeks on/1 week off) + LET (2.5 mg/day); men and premenopausal women received concomitant goserelin (3.6-mg subcutaneous implant every 28 days). The primary outcome was safety and tolerability. A pre-planned interim analysis was conducted ˜15 months after first patient first visit. Results: Of the first 1,008 patients enrolled who completed 56 days of follow-up or discontinued before the data cut-off date, 377 were ≥65 years of age. Of these, 157 (41.6%) were 65-<70 years, 107 (28.4%) were 70-<75 years, and 113 (30%) were ≥75 years. The majority of patients (94.4%) had an Eastern Cooperative Oncology Group performance status ≤1; 33.2% presented with stage IV disease at diagnosis; 9 patients were male. The most common sites of metastasis were bone (70.0%), lung (44.8%), and lymph nodes (29.7%). The most common all-grade adverse events (AEs) were neutropenia (58.4%), nausea (31.8%), and fatigue (24.1%). The most common grade 3/4 AEs were neutropenia (37.7%) and alanine aminotransferase increase (4.2%). QT prolongation events were mild (majority grade 1/2) and occurred in 6.1% of patients (0.5% grade 3/4). Dose reduction or interruption due to AEs occurred in 54.5% of patients; 6.9% of patients had AEs leading to treatment discontinuation. In the overall patient population, the most frequent grade 3/4 AEs were neutropenia (42.8%), leukopenia (3.4%), and increased alanine aminotransferase (2.9%); QT prolongation occurred in 5.4% of patients (0.5% grade 3/4). Conclusions: Initial safety results from CompLEEment-1, from the first 56 days of follow-up, demonstrate the tolerability of RIBO+LET in older patients, consistent with the overall patient population. NCT02941926. Citation Format: Ring A, Borstnar S, Ferreira A, Azim HA, Cottu P, Lu J, Martin M, Zamagni C, Beck JT, Zhou K, Wu J, Menon L, De Laurentiis M. Ribociclib (RIBO) + letrozole (LET) in older patients with hormone receptor-positive (HR+), human epidermal growth factor receptor-2–negative (HER2–) advanced breast cancer (ABC): Preliminary subgroup results from the phase 3b CompLEEment-1 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-16.

Abstract P6-18-15: Ribociclib + endocrine therapy in hormone receptor-positive, HER2-negative advanced breast cancer: A pooled safety analysis

Abstract Background: In Phase III trials, ribociclib (RIB; cyclin-dependent kinase 4/6 inhibitor) + various endocrine therapy (ET) partners has demonstrated significantly prolonged progression-free survival vs placebo (PBO) + ET in patients (pts) with hormone receptor-positive (HR+), HER2-negative (HER2–) advanced breast cancer (ABC). Here we further evaluate the safety of RIB-based regimens of interest for the proposed indication (i.e. with a non-steroidal aromatase inhibitor [NSAI] or fulvestrant [FUL]) using pooled data from three Phase III trials (MONALEESA [ML]-2 [NCT01958021], -3 [NCT02422615], and -7 [NCT02278120]). Methods: Postmenopausal pts with HR+, HER2– ABC received RIB (600 mg/day; 3-weeks-on/1-week-off) or PBO + letrozole (LET; 2.5 mg/day; ML-2 [no prior ET for ABC]) or FUL (500 mg, Days 1 and 15 of Cycle 1, then Day 1 of every cycle thereafter; ML-3; no or ≤1 prior line of ET for ABC]). Premenopausal pts (ML-7; no prior ET and ≤1 chemotherapy for ABC]) received RIB or PBO + anastrozole (1 mg/day)/LET (2.5 mg/day) + goserelin (3.6 mg every 28 days). Adverse events (AEs) were characterized per Common Terminology Criteria for Adverse Events v4.03; safety analyses included time to first event, duration of event, and rate of associated RIB/PBO discontinuations. Results: Data for 1883 pts were pooled; 1065 pts received RIB + ET and 818 pts received PBO + ET (median exposure to study treatment: 17 and 13 months, respectively). Exposure-adjusted incidence rates for AEs of special interest were 561 and 131 per 100 pt-years in the RIB and PBO arms, respectively. The most common all-causality Grade 3/4 AEs (≥10% in any arm; RIB vs PBO) were neutropenia (59% vs 2%), leukopenia (18% vs 1%), and hypertension (13% vs 13%). A new Fridericia's corrected QT interval (QTcF) >480 ms occurred in (n/N) 52/1054 (5%) vs 11/814 (1%) pts in the RIB vs PBO arms; a new QTcF >500 ms occurred in 14/1054 (1%) vs 1/814 (<1%) pts. Median time to first event for Grade ≥2 neutropenia, elevated alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), and QTc prolongation in the RIB arm was 2, 12, and 2 weeks, respectively; median duration of first Grade ≥2 event was 4, 4, and 2 weeks. In the RIB arm vs PBO arms, 7% vs 3% of pts discontinued study treatment due to AEs; common all-grade AEs leading to RIB/PBO discontinuation (≥2% in any arm) were elevated ALT (4% vs <1%) and elevated AST (2% vs 1%). Discontinuation due to QT prolongation occurred in 4 pts in the RIB arm and 2 in the PBO arm (both <1%). All-grade serious AEs occurred in 25% of pts in the RIB arm vs 15% of pts in the PBO arm. Conclusions: RIB in combination with various ET partners continues to demonstrate a predictable and manageable tolerability profile across a broad population of pts with HR+, HER2– ABC. Citation Format: Burris HA, Chan A, Im S-A, Chia S, Tripathy D, Esteva FJ, Campone M, Bardia A, Kong O, Bao W, Diaz-Padilla I, Rodriguez Lorenc K, Yardley DA. Ribociclib + endocrine therapy in hormone receptor-positive, HER2-negative advanced breast cancer: A pooled safety analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-15.

Abstract GS3-08: Alpelisib + fulvestrant for advanced breast cancer: Subgroup analyses from the phase III SOLAR-1 trial

Abstract Background: Hyperactivation of the phosphatidylinositol-3-kinase (PI3K) pathway can occur due to PIK3CA mutations, present in ~40% of patients (pts) with hormone receptor-positive (HR+), human epidermal growth factor receptor 2-negative (HER2—) ABC. SOLAR-1, a Phase 3 randomized, double-blind trial (NCT02437318), investigated efficacy and safety of ALP (α-specific PI3K inhibitor) + FUL in pts with HR+, HER2— ABC. ALP+FUL met the primary endpoint by significantly extending progression-free survival (PFS) vs placebo (PBO) + FUL in the PIK3CA-mutant cohort (hazard ratio [HR] 0.65; 95% CI 0.50—0.85; p=0.00065; median 11.0 vs 5.7 months). Here we report overall survival (OS), subgroup data and safety in the PIK3CA-mutant cohort, and PFS by circulating tumor (ct)DNA PIK3CA mutation status in the total population. Methods: Enrollment was open to men/postmenopausal women with PIK3CA-mutant HR+, HER2— ABC and 1 prior line of endocrine therapy. Pts were randomized (1:1) to ALP (300mg/day) + FUL (500mg every 28 days and Cycle 1 Day 15) or PBO+FUL. OS was the key secondary endpoint. PFS was analyzed by PIK3CA mutant status in ctDNA, and in important prognostic subgroups, including line of treatment in ABC and prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) use. Safety was analyzed in the PIK3CA-mutant cohort. Results: 341 pts in the PIK3CA-mutant cohort received ALP+FUL (n=169) or PBO+FUL (n=172). Median follow-up from randomization to data cut-off was 20.0 months. At data cut-off, 92 deaths had occurred (52% of the total 178 pts planned for final OS analysis); 40 for ALP+FUL (24%) and 52 for PBO+FUL (30%). OS results were immature at data cut-off (HR 0.73; 95% CI 0.48—1.10; p=0.06; median not estimable vs 26.9 months). There was a 45% risk reduction in PFS for pts with ctDNA PIK3CA mutations (HR 0.55; 95% CI 0.39—0.79; n=186); 20% for pts without (HR 0.80; 95% CI 0.60—1.06; n=363). PFS treatment effect for ALP+FUL vs PBO+FUL was generally consistent across subgroups of interest, with a risk reduction of 29% for pts receiving first-line (1L) treatment (HR 0.71; 95% CI 0.49—1.03; n=177), and 39% for 2L treatment (HR 0.61; 95% CI 0.42—0.89; n=161); 52% in pts with prior CDK4/6i (HR 0.48; 95% CI 0.17—1.36; n=20) and 33% in pts without (HR 0.67; 95% CI 0.51—0.87; n=321). Most frequent all-grade adverse events (AEs; ≥40% in either arm by single preferred term; ALP+FUL vs PBO+FUL) were hyperglycemia (65% vs 9%), diarrhea (54% vs 11%), nausea (46% vs 20%), and rash (40% vs 6%). Grade 3/4 AEs in ≥10% pts in either arm were hyperglycemia (fasting plasma glucose >250mg/dL; 37% for ALP+FUL vs <1% for PBO+FUL) and rash (13% vs <1%); discontinuations of ALP+FUL/PBO+FUL due to AEs were 3% vs 2%. Conclusions: ALP+FUL showed consistent clinically meaningful treatment benefit for pts with ctDNA PIK3CA mutant status, and across pt subgroups, including pts with/without prior treatment for ABC and prior CDK4/6i use. OS data were not yet mature at the data cut-off, but OS appeared numerically longer for ALP+FUL vs PBO+FUL after 52% of events. Key words: advanced breast cancer; PI3K; alpelisib; endocrine therapy Citation Format: Juric D, Ciruelos E, Rubovszky G, Campone M, Loibl S, Rugo HS, Iwata H, Conte P, Mayer IA, Kaufman B, Yamashita T, Lu Y-S, Inoue K, Takahashi M, Pápai Z, Longin A-S, Mills D, Wilke C, Sellami D, Andre F. Alpelisib + fulvestrant for advanced breast cancer: Subgroup analyses from the phase III SOLAR-1 trial [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr GS3-08.

Abstract P6-18-34: Treat ER+ight Canadian prospective observational study in HR+ advanced breast cancer: 3rd interim analysis

Abstract Treat ER+ight is the 1st prospective observational study in Canadian HR+ HER2– advanced breast cancer patients currently receiving endocrine therapy (ET) alone or in combination with targeted therapy (TT) in the first, second or third line setting (NCT02753686). Methods: This pre-planned interim analysis describes baseline characteristics, treatment patterns and safety/toxicity of patients enrolled in ET and ET+TT cohorts. At data cut-off (November 2017), 200 patients were enrolled from 24 sites since March 2016. The median follow-up time at data cut-off was 8.1 months and 182 patients were evaluable for this analysis. Results: ET (n=73)ET + TT (n=109)Baseline Patient and Disease Characteristics Median age, years (range)71 (37-92)65 (39-87), p=0.017ECOG 0-1 (%)6274Median time since primary BC diagnosis, years (range)5 (0-37)6 (0-31)Median time with advanced BC diagnosis, years (range)1 (0-16)1 (0-8)Sites of Metastases (%) Bone only4027Visceral6073Location of Metastases (%) Lungs5747Liver2348, p=0.006Bone4846Lymph Nodes2735Enrollment Therapy (%) Everolimus+exemestane-29Fulvestrant17-Palbociclib+letrozole-16Palbociclib+fulvestrant-12Tamoxifen11-Exemestane6-Letrozole3-Anastrozole2-Palbociclib+exemestane-1Everolimus+tamoxifen-0.5Unknown11Start Dose of Targeted Therapy Everolimus (n=53); 10, 7.5, 5mg (%)-72, 4, 24Palbociclib (n=54); 125, 100mg, unknown (%)-89, 9, 2On-Study Adverse Events ≥15% (all-grade, %) Fatigue2332Nausea1224Diarrhea1120Cough815Alopecia316Neutropenia017 Conclusions: The majority of patients enrolled (64%) were receiving endocrine-based targeted therapy (CDK4/6 inhibitor or mTOR inhibitor) combinations. ET+TT patients were younger with more visceral disease and liver metastases compared to patients receiving endocrine therapy alone. Real-world starting dose of targeted therapies appears to be lower than the approved full dose for 11% of patients receiving palbociclib and 28% of patients receiving everolimus. Incidence of reported all-grade adverse events appears to be lower than previously reported in randomized trials and may be a consequence of real-world under-reporting of adverse events as well as the heterogeneous nature of the treatment cohorts. There does however appear to be a trend toward increased incidence of adverse events in the ET+TT cohort compared to the ET cohort. Citation Format: Doyle C, Califaretti N, Dent S, Iqbal N, Mates M, Kulkarni S, Bains P, Glenns V, Perri SR, Chia S. Treat ER+ight Canadian prospective observational study in HR+ advanced breast cancer: 3rd interim analysis [abstract]. In: Proceedings of the 2018 San Antonio Breast Cancer Symposium; 2018 Dec 4-8; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2019;79(4 Suppl):Abstract nr P6-18-34.

A multicenter, phase Ib/2 study of varlitinib plus gemcitabine and cisplatin (gem/cis) for treatment of naïve, advanced, or metastatic biliary tract cancer (BTC).

319 Background: BTC is a rapidly progressing cancer with limited response to chemotherapy. First line therapy (gem/cis) was defined in the ABC-02 study (Valle et al), where a 26% response was seen. HER family receptors are overexpressed and may be involved in tumour proliferation and survival in BTC. Varlitinib, a reversible tyrosine kinase inhibitor of EGFR, HER2, and HER4, shows potent activity as monotherapy in preclinical BTC models and clinical activity in BTC patients (pts) in phase (ph) 1 trials. We conducted a ph Ib/2 study of varlitinib plus gem/cis in BTC to understand the safety profile and determine the maximum tolerated dose (MTD) of the combination. Methods: A modified 3+3+3 escalation design was used in Ph1b, with 2 varlitinib dose levels (200 and 300 mg BID) plus gem/cis on Day 1 and 8 in a 3 week cycle. The primary objectives are to determine the MTD and to characterize the safety profile. Secondary objectives are to assess the preliminary efficacy and to evaluate the pharmacokinetics of varlitinib and any circulating metabolites. Results: As of 10 Sep 2018, 21 pts were enrolled (11 in 200 mg cohort and 10 in 300 mg cohort, with 9 and 4 evaluable for MTD, respectively). Dose limiting toxicities (DLTs) were observed in 3 pts (1 G3 unconjugated hyperbilirubinemia and 1 G3 ALT transaminitis/G4 AST transaminitis in 200 mg cohort; 1 G4 thrombocytopenia/G3 febrile neutropenia/G3 AST elevation in 300 mg cohort). In 19 pts who were on varlitinib ≥ 1 month, 7 had partial response and 10 achieved stable disease (all > 12 weeks), giving the overall response rate of 37% and the disease control rate of 89%. The median PFS for the 200 mg cohort was 248 days and was not reached for the 300 mg cohort. The most common (≥ 30%) all-grade adverse events (AEs) regardless of causality were thrombocytopenia (62%), neutropenia (52%), anorexia (38%), nausea (38%), diarrhoea (38%), and anaemia (33%); the most common (≥ 15%) grade ≥ 3 AEs were neutropenia (48%), thrombocytopenia (33%), and anaemia (19%). Conclusions: Varlitinib plus gem/cis was well tolerated in the 200 mg cohort; the 300 mg cohort is ongoing. Preliminary anti-tumour activity was observed. Data will be updated at the time of presentation. Clinical trial information: NCT02992340.

Safety of Vinflunine in Patients with Advanced Urothelial Carcinoma Refractory to Platinum-based Chemotherapy: A Prospective Pilot Study.

Several single chemotherapeutic agents have been evaluated as the second-line treatment of advanced urothelial carcinoma. Despite encouraging efficacy outcomes, toxicity has often led to dose modifications or discontinuation. We aimed to assess the safety of vinflunine in a particular population of advanced transitional cell carcinoma of urothelium (TCCU), that were exposed to the previous toxicity of chemotherapy. This is an open-label, prospective, single-center pilot study to evaluate the response rate and safety profile of vinflunine in patients with advanced TCCU. It was planned to enroll 25 evaluable patients. Eligible patients are those with progressive disease after first-line platinum-based regimen for advanced or metastatic disease. The study was prematurely closed due to two sudden deaths that were judged by the review board as treatment-related. Only ten patients were evaluated and received at least one cycle of vinflunine. All but one were male and seven underwent radical surgery. Eight had a distant metastasis (mainly lung and/or liver). Disease control rate was 40%, four patients had a partial response with median duration of response of 3.5 months. The median overall survival was 3.2 months (95% CI:1.67- 4.73). There were three serious adverse events namely two sudden deaths and one grade 4 thrombocytopenia. Nine grade 3/4 adverse events occurred. The most common all-grade adverse events were fatigue (50%), constipation (40%) and vomiting (40%). Moreover, grade 3 fatigue occurred in 30% of patients. Only one patient, who achieved PR for 5 months, was fit to receive further cytotoxic chemotherapy. The activity of vinflunine in advanced urothelial carcinoma came at the expense of its safety. The use of vinflunine has to be limited to the selected group of patients. However, this is a single institute experience in a limited number of patients.

Safety and activity of ibrutinib in combination with nivolumab in patients with relapsed non-Hodgkin lymphoma or chronic lymphocytic leukaemia: a phase 1/2a study

Preclinical studies have shown synergistic antitumour effects between ibrutinib and immune-checkpoint blockade. The aim of this study was to assess the safety and activity of ibrutinib in combination with nivolumab in patients with relapsed or refractory B-cell malignant diseases. We did a two-part, open-label, phase 1/2a study at 21 hospitals in Australia, Israel, Poland, Spain, Turkey, and the USA. The primary objective of part A (dose escalation) was to assess the safety of daily oral ibrutinib (420 mg or 560 mg) in combination with intravenous nivolumab (3 mg/kg every 2 weeks) to ascertain a recommended phase 2 dose in patients with relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, or diffuse large B-cell lymphoma. Dose optimisation was investigated using a modified toxicity probability interval design. The primary objective of the part B expansion phase was to establish the preliminary activity (the proportion of patients who achieved an overall response) of the combination of ibrutinib and nivolumab in four cohorts: relapsed or refractory high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma (del17p or del11q), follicular lymphoma, diffuse large B-cell lymphoma, and Richter's transformation. All participants who received at least one dose of treatment were included in the primary analysis and analyses were done by disease cohort. This trial is registered with ClinicalTrials.gov, number NCT02329847. The trial is ongoing. Between March 12, 2015, and April 11, 2017, 144 patients were enrolled in the study. Three patients died before receiving study treatment; thus, 141 patients were included in the analysis, 14 in part A and 127 in part B. One dose-limiting toxicity (grade 3 hyperbilirubinaemia) was reported at the 420 mg dose in the diffuse large B-cell lymphoma cohort, which resolved after 5 days. The combination of ibrutinib and nivolumab led to overall responses in 22 (61%) of 36 patients with high-risk chronic lymphocytic leukaemia or small lymphocytic lymphoma, 13 (33%) of 40 patients with follicular lymphoma, 16 (36%) of 45 patients with diffuse large B-cell lymphoma, and 13 (65%) of 20 patients with Richter's transformation. The most common all-grade adverse events were diarrhoea (47 [33%] of 141 patients), neutropenia (44 [31%]), and fatigue (37 [26%]). 11 (8%) of 141 patients had adverse events leading to death; none were reported as drug-related. The most common grade 3-4 adverse events were neutropenia (40 [28%] of 141 patients) and anaemia (32 [23%]). The incidence of grade 3-4 neutropenia ranged from eight (18%) of 45 patients with diffuse large B-cell lymphoma to 19 (53%) of 36 patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma; incidence of grade 3-4 anaemia ranged from five (13%) of 40 patients with follicular lymphoma to seven (35%) of 20 patients with Richter's transformation. The most common serious adverse events included anaemia (six [4%] of 141 patients) and pneumonia (five [4%]). The most common grade 3-4 immune-related adverse events were rash (11 [8%] of 141 patients) and increased alanine aminotransferase (three [2%]). The combination of ibrutinib and nivolumab had an acceptable safety profile and preliminary activity was similar to that reported with single-agent ibrutinib in chronic lymphocytic leukaemia or small lymphocytic lymphoma, follicular lymphoma, and diffuse large B-cell lymphoma. The clinical response in patients with Richter's transformation was promising and supports further clinical assessment. Janssen R&D.