Consolidation Durvalumab Improves PFS in Unresectable Stage III NSCLC Without Progression After CRT

The use of durvalumab (Imfinzi) as a consolidation therapy improved progression-free survival (PFS) over placebo in patients with locally advanced, unresectable non–small cell lung cancer (NSCLC) who did not experience disease progression after concurrent or sequential platinum-based chemoradiotherapy (CRT), according to data from the phase 3 PACIFIC-5 study (NCT03706690) presented during the 2024 ESMO Asia Congress.1

At a median follow-up of in censored patients who received durvalumab (n = 252) was 35.7 months vs 30.5 months in those who received placebo (n = 129). The median PFS was 14.0 months (95% CI, 10.9-18.0) by blinded independent central review (BICR) in the durvalumab arm vs 6.5 months (95% CI, 5.4-13.8) in the placebo arm, translating to a 25% reduction in the risk of disease progression or death (HR, 0.75; 95% CI, 0.58-0.99; P = .038).

Subgroup analysis showed consistent PFS benefit irrespective of whether patients had received concurrent or sequential CRT. In those who received concurrent CRT, the median PFS with durvalumab (n = 168) was 16.5 months (95% CI, 11.0-26.9) by BICR vs 9.5 months (95% CI, 5.6-16.6) with placebo (n = 90; HR, 0.76; 95% CI, 0.55-1.06; P = .103). In those who received sequential CRT, the median PFS in the durvalumab (n = 84) and placebo (n = 39) arms was 11.0 months (95% CI, 5.6-16.4) and 5.4 months (95% CI, 3.6-7.9), respectively (HR, 0.75; 95% CI, 0.49-1.18; P = .213).

A trend toward improved overall survival (OS) was also observed with durvalumab vs placebo, at a median OS of 38.3 months (95% CI, 28.9-42.8) and 32.5 months (95% CI, 20.6-40.4), respectively (HR, 0.87; 95% CI, 0.66-1.17; P = .346).

“PACIFIC-5 supports the use of consolidation immunotherapy after either concurrent or sequential CRT, consistent with the PACIFIC trial [NCT02125461] and real-world evidence,” Yi-Long Wu, MD, of Guangdong Lung Cancer Institute, Guangdong Provincial People’s Hospital, Southern Medical University and Guangdong Provincial Key Laboratory of Translational Medicine in Lung Cancer, in Guangzhou, China, said in a late-breaking presentation of the data.

For patients with unresectable, stage III NSCLC, consolidation durvalumab following concurrent CRT is the standard of care. Although concurrent CRT is linked with better OS than sequential CRT, many patients still receive the latter approach in practice, according to Wu. Because patients receiving sequential CRT were not included on the phase 3 PACIFIC trial, there is limited evidence supporting immunotherapy following sequential CRT in this setting. Prospective data regarding the PACIFIC regimen in regions such as China, Russia, and other areas in Asia, are also needed, as these patients are not heavily represented in prior studies conducted.

The double-blind, placebo-controlled, multicenter, phase 3 PACIFIC-5 study enrolled patients with unresectable, stage III NSCLC who did not experience disease progression after concurrent or sequential CRT. These patients had an ECOG performance status of 0 or 1 and must have had data available on PD-L1 expression as well as EGFR and ALK mutational status. A total of 407 patients comprised the intention-to-treat (ITT) population, and 381 comprised the modified ITT (mITT) population; those in the latter population were all randomized patients who did not have sensitizing EGFR mutations or ALK rearrangements.

Patients were randomly assigned 2:1 to receive durvalumab at 1500 mg or placebo every 4 weeks until disease progression. They were stratified based on type of CRT (concurrent vs sequential) and PD-L1 tumor cell (TC) expression (≥1% vs <1%). The primary end point of the study was PFS by BICR and RECIST 1.1 criteria in the mITT population, and a key secondary end point was OS in the same population.

In the mITT population, the median patient age in the durvalumab and placebo arms was 63.0 years (range, 33-80); most were male (92.1% vs 88.4%), Asian (71.4% vs 72.9%), current or former smokers (84.9% vs 88.4%), had an ECOG performance status of 1 (68.3% vs 55.0%), and squamous histology (69.8% vs 65.1%). More patients in the durvalumab arm had stage IIIC disease at study entry per American Joint Committee on Cancer criteria (23.4% vs 14.7%). Regarding PD-L1 TC expression, in the durvalumab arm, 40.1% had expression less than 1% and 59.9% had expression of 1% or higher; in the placebo arm, the respective rates were 39.5% and 60.5%.

“Prior radiotherapy and chemotherapy characteristics were balanced between the 2 arms,” Wu noted.

In the durvalumab arm, 99.6% of patients received durvalumab and 19.1% were still receiving the agent at the time of the data cutoff date of June 23, 2024. Of those who discontinued treatment in this arm (n = 203), the most common reason was disease progression (53.4%), followed by toxicity (14.3%), patient decision (6.0%), other (4.8%), COVID-19 pandemic (1.2%), and severe non-compliance to trial protocol (1.2%). In the placebo arm, 99.2% of patients received placebo and 17.2% were receiving placebo at the time of data cutoff. Of the patients who discontinued placebo (n = 106), the most common reason for discontinuation was progressive disease (66.4%), followed by patient decision (7.8%), toxicity (7.0%), and other (1.6%).

Additional efficacy data showed that the 12-month PFS rates in the durvalumab and placebo arms were 53.6% and 42.7%, respectively; the 24-month PFS rates were 39.9% and 30.2%. Within the population of patients who had received concurrent CRT, the 12-month PFS rates in the durvalumab and placebo arms were 56.5% and 49.2%; the rates at 24 months were 43.4% and 34.9%. In the population of patients who received sequential CRT, the 12-month PFS rates in the durvalumab and placebo arms were 47.9% and 28.3%; the 24-month rates were 33.1% and 19.8%.

In the mITT population, the 12-month OS rate in the durvalumab arm was 80.9% vs 75.8% in the placebo arm; at 24 months, these respective rates were 60.7% and 54.4%.

“Approximately half of patients in the durvalumab arm received a year of treatment,” Wu said. “Almost one-third of patients in the durvalumab arm remained on treatment at 2 years.”

Regarding safety, adverse effects (AEs) were noted to align with what is typically observed with single-agent durvalumab in those with prior receipt of CRT. Any AEs were reported in 94.8% of those in the durvalumab arm vs 83.6% of those in the placebo arm; 63.5% and 39.6% were causally related to study treatment. Any AE of a maximum of grade 3 or 4 occurred in 26.9% and 23.9% of patients in the durvalumab and placebo arms, respectively; 8.5% and 3.7% were causally related to study treatment. Immune-mediated AEs occurred in 27.7% and 14.9% of patients, respectively; these effects were grade 3 or 4 for 4.1% and 0% of patients.

AEs led to treatment discontinuation for 14.4% of those in the durvalumab arm and 8.2% of those in the placebo arm. Serious AEs occurred in 38.4% and 33.6% of those in the durvalumab and placebo arms, respectively. AEs proved fatal for 9.2% of those in the durvalumab arm and 1.5% of those in the placebo arm; 4 in the durvalumab arm were determined to be causally related to treatment.

The most common AEs experienced by at least 10% of patients in the durvalumab (n = 271) and placebo (n = 134) arms were pneumonitis or radiation pneumonitis (39.5% vs 40.3%), pneumonia (18.8% vs 11.2%), hypothyroidism (18.8% vs 7.5%), anemia (15.1% vs 14.9%), COVID-19 (12.9% vs 11.2%), cough (11.8% vs 11.9%), upper respiratory tract infection (11.4% vs 11.9%), hyperthyroidism (12.2% vs 6.0%), and increased alanine aminotransferase level (10.0% vs 4.5%).

When broken down further, pneumonitis in the durvalumab arm was grade 1 for 15.5% of patients, grade 2 for 18.8% of patients, grade 3 for 3.7% of patients, and grade 5 for 1.5% of patients; these respective rates in the placebo arm were 14.9%, 22.4%, 2.2%, and 0.7%.

Disclosures: Dr Wu disclosed receiving a research grant (institution) from AstraZeneca, Boehringer Ingelheim, Bristol Myers Squibb, Hengrui, and Roche; and serving in a speaker, consulting or advisory role for AstraZeneca, BeiGene, Boehringer Ingelheim, Bristol Myers Squibb, Eli Lilly and Company, Merck Sharp & Dohme, Pfizer, Roche, and Sanofi. The PACIFIC-5 study is sponsored by AstraZeneca.

Reference

Wu Y-L, Wu L, Bi N, et al. PACIFIC-5: a phase 3 study of consolidation durvalumab in patients with unresectable stage III NSCLC and no progression after concurrent or sequential chemoradiotherapy. Ann Oncol. 2024;35(suppl 4):S1624. doi:10.1016/j.annonc.2024.10.643