ASCO Highlights for Tuesday June 4, 2019

As the 2019 American Society of Clinical Oncology (ASCO) Annual Meeting comes to an end, one of today’s final sessions included follow-up data from a phase 1b study of acalabrutinib and obinutuzumab in chronic lymphocytic leukemia (CLL), endpoint analyses of the phase 3 CLL-14 trial, and results of the phase 2 ORIENT-4 trial in NK/T cell lymphoma.

High and durable response rates with acalabrutinib plus obinutuzumab in CLL (Abstract 7500)

This open-label, phase 1b/2 trial (NCT02296918) evaluated acalabrutinib plus obinutuzumab in patients with treatment-naïve (n=19) or relapsed, refractory (n=26) CLL.

Primary endpoints were overall response rate (ORR) and safety. Minimal residual disease negativity (MRD–) was assessed at a sensitivity of 10-4. Common grade 3 and 4 adverse events (AE) included decreased neutrophil count (24%), syncope (11%), decreased platelet count, increased weight, and cellulitis (9% each). There were 2 (4%) grade 3 bleeding events and one (2%) grade 3 atrial fibrillation event.

With a median follow-up of about 3.5 years ORR was 95%, with 31.6% complete responses (CR) in the treatment-naïve patients and 92% with 7.7% CR in the relapsed, refractory patients. Neither median duration of response nor median progression-free survival (PFS) were reached in either group. MRD– in the bone marrow at day 1 of cycle 12 occurred in 26% of treatment-naïve patients and in 15% of those with relapsed refractory CLL.

Acalabrutinib plus obinutuzumab was well tolerated with no new safety signals and resulted in high response rates that were durable and deepened over time.

Fixed-duration venetoclax plus obinutuzumab induced MRD-negativity in previously treated CLL (Abstract 7502)

CLL-14, a phase 3, open-label trial (NCT02242942) compared fixed-duration venetoclax plus obinutuzumab to chloramabucil plus obinutuzumab in previously untreated patients with CLL and comorbidities typical of the CLL population, defined as a cumulative illness rating score (CIRS) >6 or an estimated creatinine clearance <70 mL/min. Patients were randomly assigned to 12 cycles of chlorambucil (n=216) or venetoclax (n=216) in combination with obinutuzumab for the first 6 cycles.

Progression-free survival (PFS) was the primary endpoint. MRD– in peripheral blood or bone marrow 3 months after end of treatment was a secondary endpoint. MRD– was analyzed every three months by an allele-specific polymerase chain reaction assay (ASO-PCR, cut-off 10-4) or by next generation sequencing (NGS, cut-offs 10-4, 10-5, 10-6).

At a median follow-up of 28 months, PFS was significantly longer in the venetoclax arm (88%) vs the chlorambucil arm (64%; HR 0.35; 95% CI 0.23-0.53; P<.0001). There was no difference in overall survival (OS) between arms.

MRD– by ASO-PCR was significantly higher in the venetoclax arm vs chlorambucil in both blood (76% vs 35%; P<.0001) and bone marrow (57% vs 17%; P<.0001) 3 months after treatment end. More patients in the venetoclax arm had MRD– in both blood and bone marrow (75% vs 49% in the chlorambucil arm), and a landmark analysis showed that MRD- in the blood was associated with longer PFS.

Higher, earlier, and more durable MRD– rates occurred in the venetoclax group; 81% had MRD negativity at 12 months after treatment end vs 27% in the chlorambucil arm (HR for MRD conversion 0.19; 95% CI 0.12-0.30; median time off treatment 18 months). MRD– by NGS was also higher in the venetoclax arm than in the chlorambucil arm (78% vs 34% at <10-4).

AE were similar between group; neutropenia was notable, and febrile neutropenia was low.

Fixed duration venetoclax plus obinutuzumab resulted in prolonged PFS associated with deep, high, and durable MRD– and low conversion to MRD positivity at one 1-year post-treatment in this patient population.

Sintilimab shows promise for relapsed, refractory extranodal NK/T cell lymphoma (Abstract 7504)

Sintilimab, an anti-PD-1 monoclonal antibody, was approved in China in 2018 to treat relapsed, refractory classical Hodgkin lymphoma. ORIENT-4, a single-arm, phase 2 trial (NCT03228836), evaluated the efficacy and safety of single agent sintilimab in relapsed, refractory extranodal NK/T cell lymphoma, which has a dismal prognosis after relapse, is more common in Asia than in North America and Europe, and has high levels of PD-L1 expression.

Patients (n=28) received sintilimab after failure of prior L-asparaginase and a median of 3 prior therapies. ORR was 67.9% with 7.1% CR, and disease control rate was 85.1%. The 1-year overall survival (OS) was 82.1%; median OS was not reached at a follow-up of 15.4 months, and 19 patients continue on study.

Grade 3 decreased lymphocyte count occurred in 2 patients; there were no grade 4 or 5 AE and no anti-drug antibodies. QoL significantly improved from baseline throughout the study.

Sintilimab was associated with early disease progression by PET in 5 patients who went on to experience CR (n=1) or partial response; this possible pseudoprogression requires further study.

By Lynne Lederman, PhD

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