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ORLANDO -- The addition of durvalumab (Imfinzi) to neoadjuvant chemotherapy followed by adjuvant treatment with the PD-L1 inhibitor alone could become a new standard option for resectable non-small cell lung cancer (NSCLC), according to interim findings from a randomized study.

In the , which met both its primary endpoints, the durvalumab-based strategy significantly improved pathologic complete response (pCR) rates and event-free survival (EFS; HR 0.68, 95% CI 0.53-0.88, P=0.0039) compared with neoadjuvant chemotherapy alone plus placebo, reported John Heymach, MD, of the University of Texas MD Anderson Cancer Center in Houston.

Rates of pCR were four times higher with durvalumab (17.2% vs 4.3%, P=0.000036), while EFS rates at 2 years reached 63.3% in the durvalumab arm versus 52.4% in the placebo arm, Heymach said at the American Association for Cancer Research (AACR) annual meeting here.

"AEGEAN is the first phase III study to demonstrate a benefit of perioperative immunotherapy plus neoadjuvant chemotherapy," said Heymach during a press briefing. "It is a potential new treatment for patients with resectable NSCLC."

'A' New Standard Option

This "is the second large randomized trial that demonstrates the value of immunotherapy in the neoadjuvant setting," said AACR discussant Roy Herbst, MD, PhD, of the Yale School of Medicine in New Haven, Connecticut, who said the "positive, early" results with the strategy represents a new standard in operable NSCLC, but with the emphasis on "a."

Herbst pointed out that the durvalumab regimen was not compared with the current standard of care as defined by CheckMate-816, which last year led to approval of neoadjuvant nivolumab (Opdivo) plus chemotherapy in resectable NSCLC.

But the new trial showed that "the incorporation of adjuvant therapy is feasible and generally safe," said Herbst, with the proviso that the data are still early, and additional trial maturity is needed to better understand the benefit of the extra post-operative therapy.

"And more work is needed to better identify and evaluate pathologic biomarkers of response and future therapy," he added.

Study Details

The international phase III AEGEAN trial randomized 802 patients to receive the durvalumab-based strategy or neoadjuvant chemotherapy alone plus matching placebo (given before and after surgery).

Durvalumab was administered at a dose of 1,500 mg every 3 weeks for four cycles prior to surgery, then every 4 weeks for up to 12 cycles following surgery. After excluding patients whose tumors had EGFR/ALK alterations, 740 patients were included in the modified intention-to-treat population and were assessed in this planned interim analysis for the co-primary endpoints of pCR and EFS.

Median age of the participants was 65, and 71.6% were men. Patients were stratified according to disease stage (II vs III) and PD-L1 tumor cell expression (about two-thirds had PD-L1 expression of at least 1%). More than 70% had carboplatin as the planned platinum agent, and about 80% in both groups ultimately underwent surgery.

Rates of major pathological response were nearly tripled with the incorporation of neoadjuvant durvalumab (33.3% vs 12.3%, P=0.000002).

With a median follow-up of 11.7 months, median EFS was not reached in the durvalumab arm versus 25.9 months in the placebo arm.

Heymach reported that the EFS benefit with the durvalumab regimen was broadly observed across prespecified subgroups (age, race, sex, histology, stage), with a greater degree of benefit in current smokers (HR 0.48, 95% CI 0.28-0.80) compared with former and non-smokers, and with cisplatin (HR 0.59, 95% CI 0.35-1.00) versus carboplatin (HR 0.73, 95% CI 0.54-0.98). The benefit in women was less clear (HR 0.95, 95% CI 0.58-1.56).

EFS improvement was also seen across PD-L1 expression levels, though most pronounced among those with expression levels of 50% or greater:

• PD-L1 <1%: HR 0.76 (95% CI 0.49-1.17)
• PD-L1 1-49%: HR 0.70 (95% CI 0.46-1.05)
• PD-L1 ≥50%: HR 0.60 (95% CI 0.35-1.01)

In terms of safety, grade 3/4 treatment-emergent adverse events were similar in the two arms (42.3% in the durvalumab arm and 43.4% in the placebo arm). Grade 3/4 adverse events possibly related to study treatment were also similar (32.3% vs 33.1%, respectively). Any-grade immune-related adverse events occurred in 23.5% of patients in the durvalumab arm versus 9.8% in the placebo arm, and were mostly low-grade events.

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