Randomized, open-label, phase 2 study of nivolumab plus ipilimumab or nivolumab monotherapy in patients with advanced or metastatic solid tumors of high tumor mutational burden.

BACKGROUND: Checkpoint inhibitor therapy has demonstrated overall survival benefit in multiple tumor types. Tumor mutational burden (TMB) is a predictive biomarker for response to immunotherapies. This study evaluated the efficacy of nivolumab+ipilimumab in multiple tumor types based on TMB status evaluated using either tumor tissue (tTMB) or circulating tumor DNA in the blood (bTMB). PATIENTS AND METHODS: Patients with metastatic or unresectable solid tumors with high (≥10 mutations per megabase) tTMB (tTMB-H) and/or bTMB (bTMB-H) who were refractory to standard therapies were randomized 2:1 to receive nivolumab+ipilimumab or nivolumab monotherapy in an open-label, phase 2 study (CheckMate 848; NCT03668119). tTMB and bTMB were determined by the Foundation Medicine FoundationOne® CDx test and bTMB Clinical Trial Assay, respectively. The dual primary endpoints were objective response rate (ORR) in patients with tTMB-H and/or bTMB-H tumors treated with nivolumab+ipilimumab. RESULTS: In total, 201 patients refractory to standard therapies were randomized: 135 had tTMB-H and 125 had bTMB-H; 82 patients had dual tTMB-H/bTMB-H. In patients with tTMB-H, ORR was 38.6% (95% CI 28.4% to 49.6%) with nivolumab+ipilimumab and 29.8% (95% CI 17.3% to 44.9%) with nivolumab monotherapy. In patients with bTMB-H, ORR was 22.5% (95% CI 13.9% to 33.2%) with nivolumab+ipilimumab and 15.6% (95% CI 6.5% to 29.5%) with nivolumab monotherapy. Early and durable responses to treatment with nivolumab+ipilimumab were seen in patients with tTMB-H or bTMB-H. The safety profile of nivolumab+ipilimumab was manageable, with no new safety signals. CONCLUSIONS: Patients with metastatic or unresectable solid tumors with TMB-H, as determined by tissue biopsy or by blood sample when tissue biopsy is unavailable, who have no other treatment options, may benefit from nivolumab+ipilimumab. TRIAL REGISTRATION NUMBER: NCT03668119.

Phase III trial of chemoradiotherapy with temozolomide plus nivolumab or placebo for newly diagnosed glioblastoma with methylated MGMT promoter.

BACKGROUND: Nearly all patients with newly diagnosed glioblastoma experience recurrence following standard-of-care radiotherapy (RT) + temozolomide (TMZ). The purpose of the phase III randomized CheckMate 548 study was to evaluate RT + TMZ combined with the immune checkpoint inhibitor nivolumab (NIVO) or placebo (PBO) in patients with newly diagnosed glioblastoma with methylated MGMT promoter (NCT02667587). METHODS: Patients (N = 716) were randomized 1:1 to NIVO [(240 mg every 2 weeks × 8, then 480 mg every 4 weeks) + RT (60 Gy over 6 weeks) + TMZ (75 mg/m2 once daily during RT, then 150-200 mg/m2 once daily on days 1-5 of every 28-day cycle × 6)] or PBO + RT + TMZ following the same regimen. The primary endpoints were progression-free survival (PFS) and overall survival (OS) in patients without baseline corticosteroids and in all randomized patients. RESULTS: As of December 22, 2020, median (m)PFS (blinded independent central review) was 10.6 months (95% CI, 8.9-11.8) with NIVO + RT + TMZ vs 10.3 months (95% CI, 9.7-12.5) with PBO + RT + TMZ (HR, 1.1; 95% CI, 0.9-1.3) and mOS was 28.9 months (95% CI, 24.4-31.6) vs 32.1 months (95% CI, 29.4-33.8), respectively (HR, 1.1; 95% CI, 0.9-1.3). In patients without baseline corticosteroids, mOS was 31.3 months (95% CI, 28.6-34.8) with NIVO + RT + TMZ vs 33.0 months (95% CI, 31.0-35.1) with PBO + RT + TMZ (HR, 1.1; 95% CI, 0.9-1.4). Grade 3/4 treatment-related adverse event rates were 52.4% vs 33.6%, respectively. CONCLUSIONS: NIVO added to RT + TMZ did not improve survival in patients with newly diagnosed glioblastoma with methylated or indeterminate MGMT promoter. No new safety signals were observed.

Phase II results from a phase I/II study to assess the safety and efficacy of weekly nab-paclitaxel in paediatric patients with recurrent or refractory solid tumours: A collaboration with the European Innovative Therapies for Children with Cancer Network.

BACKGROUND: The phase I component of a phase I/II study defined the recommended phase II dose and established the tolerability of nab-paclitaxel monotherapy in paediatric patients with recurrent or refractory solid tumours. The activity and safety of nab-paclitaxel monotherapy was further investigated in this phase II study. PATIENTS AND METHODS: Paediatric patients with recurrent or refractory Ewing sarcoma, neuroblastoma or rhabdomyosarcoma received 240 mg/m2 of nab-paclitaxel on days 1, 8 and 15 of each 28-day cycle. The primary end-point was the overall response rate (ORR; complete response [CR] + partial response [PR]). Secondary end-points included duration of response, disease control rate (DCR; CR + PR + stable disease [SD]), progression-free survival, 1-year overall survival, safety and pharmacokinetics. RESULTS: Forty-two patients were enrolled, 14 each with Ewing sarcoma, neuroblastoma and rhabdomyosarcoma. The ORRs were 0%, 0% and 7.1% (1 confirmed PR), respectively. The DCRs were 30.8% (4 SD), 7.1% (1 SD) and 7.1% (1 confirmed PR and 0 SD) in the Ewing sarcoma, neuroblastoma and rhabdomyosarcoma groups, respectively. The median progression-free survival was 13.0, 7.4 and 5.1 weeks, respectively, and the 1-year overall survival rates were 48%, 25% and 15%, respectively. The most common grade III/4IVadverse events were haematologic (neutropenia [50%] and anaemia [48%]), and grade III/IV peripheral neuropathy occurred in 2 patients (14%) in the rhabdomyosarcoma group. Pharmacokinetics analyses revealed that paclitaxel tissue distribution was both rapid and extensive. CONCLUSIONS: In this phase II study, limited activity was observed; however, the safety of nab-paclitaxel in paediatric patients was confirmed. TRIAL REGISTRATION: NCT01962103 and EudraCT 2013-000144-26.

Randomised phase 2 study of pembrolizumab plus CC-486 versus pembrolizumab plus placebo in patients with previously treated advanced non-small cell lung cancer.

INTRODUCTION: Preclinical and early clinical studies suggest that combining epigenetic agents with checkpoint inhibitors can potentially improve outcomes in patients with previously treated advanced non-small cell lung cancer (NSCLC). This phase 2 trial examined second-line pembrolizumab + CC-486 (oral azacitidine) in patients with advanced NSCLC. METHODS: Patients with one prior line of platinum-containing therapy were randomised in a ratio of 1:1 to CC-486 or placebo, on days 1-14, in combination with pembrolizumab on day 1 of a 21-day cycle. The primary end-point was progression-free survival (PFS). Key secondary end-points included overall survival (OS), overall response rate (ORR) and safety. RESULTS: Among 100 patients randomised (pembrolizumab + CC-486: 51; pembrolizumab + placebo: 49), most were male (57.0%), were white (87.0%) and had Eastern Cooperative Oncology Group performance status 1 (68.0%). No significant difference in PFS was observed between the pembrolizumab + CC-486 and pembrolizumab + placebo arms (median, 2.9 and 4.0 months, respectively; hazard ratio [HR], 1.374; 90% confidence interval [CI], 0.926-2.038; P = 0.1789). Median OS was 11.9 months versus not estimable (HR, 1.375; 90% CI, 0.830-2.276; P = 0.2968); ORR was 20% versus 14%. Median treatment duration was shorter (15.0 versus 24.1 weeks), and the number of cycles was lower (5.0 versus 7.0) with pembrolizumab + CC-486 versus pembrolizumab + placebo. No new safety signals for CC-486 or pembrolizumab were detected. Treatment-emergent adverse events were more common in the pembrolizumab + CC-486 arm, particularly gastrointestinal, potentially impacting treatment feasibility. CONCLUSIONS: No improvement in PFS was observed with pembrolizumab + CC-486 versus pembrolizumab + placebo. Decreased treatment exposure due to adverse events may have impacted efficacy with pembrolizumab + CC-486.

Phase I results of a phase I/II study of weekly nab-paclitaxel in paediatric patients with recurrent/refractory solid tumours: A collaboration with innovative therapies for children with cancer.

BACKGROUND: nab-Paclitaxel has demonstrated efficacy in adults with solid tumours and preclinical activity in paediatric solid tumour models. Results from phase I of a phase I/II study in paediatric patients with recurrent/refractory solid tumours treated with nab-paclitaxel are reported. PATIENTS AND METHODS: Patients with recurrent/refractory extracranial solid tumours received nab-paclitaxel on days 1, 8 and 15 every 4 weeks at 120, 150, 180, 210, 240, or 270 mg/m2 (rolling-6 dose-escalation) to establish the maximum tolerated dose (MTD) and recommended phase II dose (RP2D). RESULTS: Sixty-four patients were treated. Dose-limiting toxicities were grade 3 dizziness at 120 mg/m2 and grade 4 neutropenia >7 days at 270 mg/m2. The most frequent grade 3/4 adverse events were haematologic, including neutropenia (36%), leukopenia (36%) and lymphopenia (25%). Although the MTD was not reached, 270 mg/m2 was declared non-tolerable due to grade 3/4 toxicities during cycles 1-2 (neutropenia, n = 5/7; skin toxicity, n = 2/7; peripheral neuropathy, n = 1/7). Of 58 efficacy-evaluable patients, complete response occurred in one patient (2%; Ewing sarcoma) and partial responses in four patients (7%; rhabdomyosarcoma, Ewing sarcoma, renal tumour with pulmonary metastases [high-grade, malignant] and sarcoma not otherwise specified); all responses occurred at ≥210 mg/m2. Thirteen patients (22%) had stable disease (5 lasting ≥16 weeks) per RECIST. CONCLUSIONS: nab-Paclitaxel 240 mg/m2 qw3/4 (nearly double the adult recommended monotherapy dose for this schedule in metastatic breast cancer) was selected as the RP2D based on the tolerability profile, pharmacokinetics and antitumour activity. Phase II is currently enrolling patients with recurrent/refractory neuroblastoma, rhabdomyosarcoma and Ewing sarcoma. CLINICALTRIALS.GOV: NCT01962103. EUDRACT: 2013-000144-26.