Atezolizumab versus chemotherapy in advanced or metastatic NSCLC with high blood-based tumor mutational burden: primary analysis of BFAST cohort C randomized phase 3 trial.

Tumor mutational burden (TMB) is being explored as a predictive biomarker for cancer immunotherapy outcomes in non-small cell lung cancer. BFAST (NCT03178552)-an open-label, global, multicohort trial-evaluated the safety and efficacy of first-line targeted therapies or immunotherapy in patients with unresectable Stage IIIB or IV advanced or metastatic non-small cell lung cancer who were selected for biomarker status using blood-based targeted next-generation sequencing. In the Phase 3 cohort C evaluating blood-based (b)TMB as a biomarker of atezolizumab efficacy, patients with bTMB of ≥10 (N = 471) were randomized 1:1 to receive atezolizumab or platinum-based chemotherapy per local standard of care. Cohort C did not meet its primary endpoint of investigator-assessed progression-free survival in the population with bTMB of ≥16 (hazard ratio, 0.77; 95% confidence interval: 0.59, 1.00; P = 0.053). Adverse events leading to treatment withdrawal occurred in 10% of patients in the atezolizumab arm and 20% in the chemotherapy arm. Adverse events of special interest occurred in 42% of patients in the atezolizumab arm and 26% in the chemotherapy arm. A prespecified exploratory analysis compared the bTMB clinical trial assay with the FoundationOne Liquid Companion Diagnostic assay and showed high concordance between assays. Additional exploration of bTMB to identify optimal cutoffs, confounding factors, assay improvements or cooperative biomarkers is warranted.

A phase 1b study of atezolizumab in combination with guadecitabine for the treatment of acute myeloid leukemia.

This phase 1 b study evaluated the safety, efficacy, and pharmacokinetics of atezolizumab in combination with guadecitabine in patients with relapsed/refractory (R/R) or first-line acute myeloid leukemia (AML). Patients received atezolizumab 840 mg (days [D] 8 and 22) and guadecitabine 60 mg/m2 (D1 and D5) over 28-day cycles. Sixteen patients (median age 73.0 years) enrolled (R/R cohort, n = 11; first-line cohort, n = 5). All patients reported at least 1 AE; 15 patients (93.8%) reported grade ≥ 3 AEs, and 15 patients (93.8%) reported SAEs. Fourteen of the 16 patients (87.5%) died during the trial period due to disease progression (8/14) or AEs (6/14), hence the study was terminated early. One patient (from the R/R AML cohort) achieved a response (CR with incomplete platelet recovery) with a DOR of 27.8 months at study termination. Atezolizumab plus guadecitabine had limited clinical activity in AML and an overall unfavorable benefit-risk profile at the investigated dose levels.

Polatuzumab Vedotin in Previously Untreated Diffuse Large B-Cell Lymphoma.

BACKGROUND: Diffuse large B-cell lymphoma (DLBCL) is typically treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). However, only 60% of patients are cured with R-CHOP. Polatuzumab vedotin is an antibody-drug conjugate targeting CD79b, which is ubiquitously expressed on the surface of malignant B cells. METHODS: We conducted a double-blind, placebo-controlled, international phase 3 trial to evaluate a modified regimen of R-CHOP (pola-R-CHP), in which vincristine was replaced with polatuzumab vedotin, as compared with standard R-CHOP, in patients with previously untreated intermediate-risk or high-risk DLBCL. Patients 18 to 80 years of age were randomly assigned in a 1:1 ratio to receive six cycles of either pola-R-CHP or R-CHOP, plus two cycles of rituximab alone. The primary end point was investigator-assessed progression-free survival. Secondary end points included overall survival and safety. RESULTS: Overall, 879 patients underwent randomization: 440 were assigned to the pola-R-CHP group and 439 to the R-CHOP group. After a median follow-up of 28.2 months, the percentage of patients surviving without progression was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% [95% confidence interval (CI), 72.7 to 80.8] vs. 70.2% [95% CI, 65.8 to 74.6] at 2 years; stratified hazard ratio for progression, relapse, or death, 0.73 by Cox regression; 95% CI, 0.57 to 0.95; P = 0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% [95% CI, 85.7 to 91.6] in the pola-R-CHP group and 88.6% [95% CI, 85.6 to 91.6] in the R-CHOP group; hazard ratio for death, 0.94; 95% CI, 0.65 to 1.37; P = 0.75). The safety profile was similar in the two groups. CONCLUSIONS: Among patients with previously untreated intermediate-risk or high-risk DLBCL, the risk of disease progression, relapse, or death was lower among those who received pola-R-CHP than among those who received R-CHOP. (Funded by F. Hoffmann-La Roche/Genentech; POLARIX ClinicalTrials.gov number, NCT03274492.).

Atezolizumab alone or in combination did not demonstrate a favorable risk-benefit profile in myelodysplastic syndrome.

We present primary results from the phase 1b GO29754 study evaluating the safety and tolerability of atezolizumab, a programmed death-ligand 1 inhibitor, alone and in combination with azacitidine, a hypomethylating agent (HMA), in patients with relapsed/refractory (R/R) or HMA-naïve myelodysplastic syndrome (MDS). Patients with R/R MDS received atezolizumab for 12 months (cohort A) or atezolizumab plus azacitidine for 6 cycles followed by atezolizumab as maintenance for 8 cycles (cohort B). Patients with HMA-naïve MDS received atezolizumab plus azacitidine until loss of clinical benefit (cohort C). Safety, activity, and exploratory end points were investigated. Forty-six patients were enrolled and received treatment (cohort A, n = 11; cohort B, n = 14; cohort C, n = 21). All patients experienced ≥1 adverse event (AE) on study, and all patients discontinued atezolizumab. In cohort A, 7 patients (63.6%) died, and no patients responded. In cohort B, 8 patients (57.1%) discontinued azacitidine, 11 (78.6%) died, and 2 (14.3%) responded. In cohort C, all 21 patients discontinued azacitidine, 13 died (61.9%), and 13 (61.9%) responded. The study was terminated by the sponsor before completion of recruitment because of the unexpected high early death rate in cohort C (6 [46.2%] of 13 deaths were due to AEs and occurred within the first 4 treatment cycles.). The high death rate and poor efficacy observed in this study do not support a favorable risk-benefit profile for atezolizumab as a single agent or in combination with azacitidine in R/R or HMA-naïve MDS. This trial was registered at www.clinicaltrials.gov as #NCT02508870.

Blood First Assay Screening Trial (BFAST) in Treatment-Naive Advanced or Metastatic NSCLC: Initial Results of the Phase 2 ALK-Positive Cohort.

INTRODUCTION: The Blood First Assay Screening Trial is an ongoing open-label, multicohort study, prospectively evaluating the relationship between blood-based next-generation sequencing (NGS) detection of actionable genetic alterations and activity of targeted therapies or immunotherapy in treatment-naive advanced or metastatic NSCLC. We present data from the ALK-positive cohort. METHODS: Patients aged more than or equal to 18 years with stage IIIB or IV NSCLC and ALK rearrangements detected by blood-based NGS using hybrid capture technology (FoundationACT) received alectinib 600 mg twice daily. Asymptomatic or treated central nervous system (CNS) metastases were permitted. Primary end point was investigator-assessed objective response rate (ORR; Response Evaluation Criteria in Solid Tumors version 1.1). Secondary end points were independent review facility-assessed ORR, duration of response, progression-free survival (PFS), overall survival, and safety. Exploratory end points were investigator-assessed ORR in patients with baseline CNS metastases and relationship between circulating biomarkers and response. RESULTS: In total, 2219 patients were screened and blood-based NGS yielded results in 98.6% of the cases. Of these, 119 patients (5.4%) had ALK-positive disease; 87 were enrolled and received alectinib. Median follow-up was 12.6 months (range: 2.6-18.7). Confirmed ORR was 87.4% (95% confidence interval [CI]: 78.5-93.5) by investigator and 92.0% (95% CI: 84.1-96.7) by independent review facility. Investigator-confirmed 12-month duration of response was 75.9% (95% CI: 63.6-88.2). In 35 patients (40%) with baseline CNS disease, investigator-assessed ORR was 91.4% (95% CI: 76.9-98.2). Median PFS was not reached; 12-month investigator-assessed PFS was 78.4% (95% CI: 69.1-87.7). Safety data were consistent with the known tolerability profile of alectinib. CONCLUSIONS: These results reveal the clinical application of blood-based NGS as a method to inform clinical decision-making in ALK-positive NSCLC.

Polatuzumab vedotin in combination with immunochemotherapy in patients with previously untreated diffuse large B-cell lymphoma: an open-label, non-randomised, phase 1b-2 study.

BACKGROUND: Polatuzumab vedotin, an antibody-drug conjugate targeting the CD79b component of the B-cell receptor, has demonstrated activity as a single agent and in combination with rituximab in relapsed or refractory diffuse large B-cell lymphoma. In this study, we evaluated the safety and preliminary activity of polatuzumab vedotin in combination with rituximab or obinutuzumab and cyclophosphamide, doxorubicin, and prednisone (CHP) in patients with previously untreated diffuse large B-cell lymphoma. METHODS: This was an open-label, non-randomised study composed of a phase 1b dose escalation and a phase 2 dose expansion at 11 hospitals and health centres in the USA and France. Patients aged 18 years or older with B-cell non-Hodgkin lymphoma were eligible. Exclusion criteria included peripheral neuropathy with grade greater than 1, major surgery within 4 weeks before enrolment, known CNS involvement of lymphoma, and uncontrolled heart disease. Phase 1b dose escalation had a three-plus-three design and established the recommended phase 2 dose. Phase 2 expansion evaluated the recommended phase 2 dose of polatuzumab vedotin in patients with newly diagnosed diffuse large B-cell lymphoma with an International Prognostic Index (IPI) of 2-5. Patients received cyclophosphamide 750 mg/m2 on day 1 intravenously, doxorubicin 50 mg/m2 on day 1 intravenously, and prednisone 100 mg once daily on days 1-5 of each 21-day cycle orally (CHP), plus either rituximab 375 mg/m2 intravenously on day 1 of each cycle (R-CHP) or obinutuzumab 1000 mg intravenously on days 1, 8, and 15 of cycle 1 and on day 1 of the following cycles (G-CHP). Polatuzumab vedotin was administered on day 2 of cycles 1 and 2, and on day 1 of the following cycles at 1·0-2·4 mg/kg during the escalation phase and at the recommended phase 2 dose during the expansion phase. Treatment could last six or eight cycles, depending on investigator preference. The primary endpoints of the study were safety and tolerability, and determination of the maximum tolerated dose (or recommended phase 2 dose) of polatuzumab vedotin. All endpoints were analysed per protocol in the safety evaluable population, defined as all patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01992653. FINDINGS: Between Dec 4, 2013, and July 26, 2016, 85 patients were enrolled. 82 patients were included in the safety and activity evaluable populations, 25 in phase 1b and 57 in phase 2. In light of information from other studies using polatuzumab vedotin reported during this study, in which the safety profile associated with exposure to polatuzumab vedotin at doses higher than 1·8 mg/kg every 3 weeks was not outweighed by any clinical benefit, the recommended phase 2 dose was set to 1·8 mg/kg in the R-CHP cohort and no higher doses were explored in this study. 66 patients with newly diagnosed diffuse large B-cell lymphoma received the polatuzumab vedotin recommended phase 2 dose (45 R-CHP; 21 G-CHP). In 66 patients with diffuse large B-cell lymphoma who received the recommended phase 2 dose, the most common adverse events of grade 3 or worse were neutropenia (20 [30%]), febrile neutropenia (12 [18%]), and thrombocytopenia (six [9%]). Among the 70 patients (any histology) who received the recommended phase 2 dose, 19 (27%) had grade 1 peripheral neuropathy, eight (11%) grade 2, and two (3%) grade 3. Four deaths were reported during follow-up: two treatment-related (one complication of atrial fibrillation and one septic shock) and two due to disease progression. As of the cutoff date of Dec 29, 2017, median follow-up time was 21·5 months (IQR 16·7-24·3) for the untreated diffuse large B-cell lymphoma cohort treated at the polatuzumab vedotin recommended phase 2 dose. 59 (89%) patients achieved an overall response at end of treatment (51 [77%] patients had a complete response, and eight [12%] patients had a partial response). INTERPRETATION: The safety of incorporating polatuzumab vedotin to R-CHP or G-CHP was as expected and managable. Preliminary clinical activity in newly diagnosed diffuse large B-cell lymphoma seems promising and encouraged a phase 3 trial comparing polatuzumab vedotin with R-CHP to R-CHOP. FUNDING: F Hoffmann-La Roche/Genentech.