Ibrutinib Addition Fails To RESOLVE Metastatic Pancreatic Cancer

Author: By Lynda Williams, Senior medwireNews Reporter 

medwireNews: The addition of ibrutinib to first-line nab-paclitaxel and gemcitabine chemotherapy does not extend overall survival (OS) for patients with metastatic pancreatic cancer, the RESOLVE investigators report. 

Margaret Tempero, from the University of California, San Francisco in the USA, and co-authors examined the combination regimen strategy following preclinical research indicating that the oral Bruton’s tyrosine kinase inhibitor might improve outcome through CD8+ T cell mechanisms and other immunological pathways.  

But the phase III trial did not show a significant difference in the median OS of the 211 treatment-naïve patients who were randomly assigned to receive ibrutinib 560 mg/day alongside chemotherapy and the 213 patients who were instead given placebo with nab-paclitaxel and gemcitabine, at a median of 9.7 and 10.8 months, respectively. 

Similarly, the rates of OS at 24 months were estimated to be 9.5% with ibrutinib plus chemotherapy and 10.5% with placebo plus chemotherapy. 

Of concern, ibrutinib was associated with a significantly shorter progression-free survival duration than placebo, at a median of 5.3 versus 6.0 months, and estimated 18-month rates were 3% and 6%, respectively. 

And the overall response rate with the use of ibrutinib was also significantly lower compared with use of placebo, at 29% versus 42%; all three complete responses to treatment occurred in the placebo arm. 

Ibrutinib was given for a shorter median duration than placebo (3.7 vs 5.5 months) and ibrutinib-treated patients, compared with controls, had a shorter median duration of treatment with both nab-paclitaxel (3.0 vs 4.5 months; 4.0 vs 5.0 cycles) and gemcitabine (3.5 vs 5.1 months; 4.0 vs 6.0 cycles). 

Thus, the use of ibrutinib versus placebo was associated with a lower median cumulative dose of both nab-paclitaxel (989.4 vs 1551.2 mg/m2) and gemcitabine (9874.5 vs 13,822.4 mg/m2).  

Nevertheless, disease progression was the most common reason for discontinuing ibrutinib/placebo, nab-paclitaxel and gemcitabine, and toxicity was comparable between the treatment arms, the researchers say. 

Grade 3 and more severe adverse events (AEs) occurred in 86% of ibrutinib-treated patients and 87% of controls. These most commonly included neutropenia (24%), peripheral sensory neuropathy (17%) and anaemia and asthenia (16% each) for the ibrutinib-treated patients and neutropenia (35%), anaemia (17%) and asthenia (12%) for those given placebo. 

Eighteen percent of patients in both treatment arms discontinued treatment because of AEs, with asthenia the most cited reason for discontinuation of ibrutinib/placebo or gemcitabine, and peripheral sensory neuropathy for nab-paclitaxel. 

“The addition of ibrutinib to nab-paclitaxel and gemcitabine may have mitigated the ability to 

deliver the complete chemotherapy regimen, as patients in the ibrutinib arm had less time on 

treatment and received a lower cumulative dose for all agents compared to patients in the 

placebo arm”, write Margaret Tempero and co-authors. 

“The differences in treatment duration and dosing of nab-paclitaxel or gemcitabine may confound our ability to interpret any potential benefit of adding ibrutinib to this chemotherapy regimen”, they postulate in the Annals of Oncology.

“However, in previous studies, ibrutinib has successfully been combined with other chemotherapeutic agents, in particular alkylating agents, for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma”, they note. 

Reference 

Tempero M, Oh D-Y, Taberno J¸ et al. Ibrutinib in combination with nab-paclitaxel and gemcitabine for first-line treatment of patients with metastatic pancreatic adenocarcinoma: Phase 3 RESOLVE Study. Ann Oncol; Advance online publication 1 February 2021. https://doi.org/10.1016/j.annonc.2021.01.070