medwireNews: Individuals with unresectable locally advanced non-small-cell lung cancer (NSCLC) and no progression after chemoradiotherapy could benefit from the addition of the CD73 inhibitor oleclumab or the NKG2A-targeted agent monalizumab to consolidation durvalumab, suggest phase 2 results.
These data were presented at the ESMO Congress 2021 by Alexandre Martinez-Marti, from Vall d’Hebron Institute of Oncology in Barcelona, Spain.
He explained that the PACIFIC trial established consolidation durvalumab as the standard of care for stage III NSCLC patients without progression after concurrent chemoradiotherapy, and continued: “Additional immunomodulation through combination therapy is being explored to improve clinical outcomes in this patient population.”
Martinez-Marti noted that radiotherapy is known to induce the expression of CD73 and NKG2A ligand, “which inhibit antitumour immune response,” and “both oleclumab and monalizumab have shown preliminary clinical activity in combination with durvalumab and cetuximab, respectively, in prior studies.”
He therefore believes there is “a strong rationale” for combining durvalumab with either of these immunomodulatory agents.
In the COAST study, 186 patients were randomly allocated to receive consolidation durvalumab at a dose of 1500 mg every 4 weeks, either as monotherapy or alongside intravenous oleclumab 3000 mg (every 2 weeks for first two cycles and every 4 weeks subsequently) or intravenous monalizumab 750 mg every 2 weeks.
Over a median follow-up of 11.5 months, the primary endpoint of investigator-assessed objective response rate was achieved by 30.0% and 35.5% of the oleclumab and monalizumab combination groups, respectively, compared with 17.9% of the durvalumab alone group.
The disease control rate at 16 weeks was similarly higher with the oleclumab and monalizumab combinations than with durvalumab alone, at 81.7% and 77.4% versus 58.2%, respectively, and progression-free survival was prolonged, with the corresponding median durations unreached, 15.1 months, and 6.3 months.
The addition of oleclumab to durvalumab was associated with a significant 56% reduction in the risk for progression or death, while the addition of monalizumab reduced the risk by a significant 35%.
Reporting on the safety, Martinez-Marti noted that “the incidence of grade 3 or higher treatment-emergent adverse events [AEs] was similar across treatment arms,” at 40.7%, 27.9%, and 39.4% with the oleclumab and monalizumab combinations and durvalumab monotherapy, respectively.
The rates of AE-related discontinuation were also comparable, at a respective 15.3%, 14.8%, and 16.7%, and one death each in the oleclumab and monalizumab combination group and two in the durvalumab alone group were considered related to study treatment.
The presenter therefore concluded: “These data support further evaluation of these combinations in a registration-intent study.”
Discussant Oliver Gautschi (Lucerne Cantonal Hospital, Switzerland) drew attention to the differing performance of durvalumab monotherapy between the COAST and PACIFIC trials, but he nonetheless believes that combination immunotherapy after chemoradiotherapy is “feasible and promising.”
Gautschi concluded that “phase 3 [trials are] justified because of the heterogeneity of non-small-cell lung cancer.”
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