Concurrent Durvalumab/CRT Does Not Confer Significant Survival Advantage in Unresectable Stage III NSCLC

Jeffrey D. Bradley, MD

Concurrent administration of durvalumab (Imfinzi) and platinum-based chemoradiotherapy (CRT) failed to produce a superior progression-free survival (PFS) or overall survival (OS) benefit and was associated with a higher number of early toxicities leading to death or discontinuation vs chemoradiation alone, in patients with unresectable stage III non–small cell lung cancer (NSCLC), according to final results from the phase 3 PACIFIC-2 trial (NCT03519971).¹

Findings were presented at the 2024 European Lung Cancer Congress. In the intention-to-treat (ITT) population, durvalumab plus CRT (n = 219) produced a median PFS of 13.8 months (95% CI, 9.5-16.9) by blinded independent central review (BICR) vs 9.4 months (95% CI, 7.5-16.6) with placebo plus CRT (n = 109; HR, 0.85; 95% CI, 0.65-1.12; P = .247). The median OS was 36.4 months (95% CI, 26.2-45.6) with the combination and 29.5 months (95% CI, 23.2-45.1) with placebo (HR, 1.03; 95% CI, 0.78-1.39; P = .823).

Notably, there was no significant difference in response rates between the durvalumab and placebo arms (P = .976), with ORRs of 60.7% (95% CI, 53.9%-67.2%) and 60.6% (95% CI, 50.7%-69.8%), respectively.

“In the first 6 months of treatment during the CRT phase, there was no difference [in PFS] between arms, and there was no early uplift with the addition of immunotherapy. Following that, there was a numerical improvement in the HR for PFS, but that did not reach statistical significance,” lead study author Jeffrey D. Bradley, MD, stated in an oral presentation of the data. Bradley is the vice chair of Proton Therapy & Technology Development and a professor of radiation oncology at the Hospital of the University of Pennsylvania in Philadelphia. “[Based on these data,] concurrent CRT followed by consolidation durvalumab, [or the PACIFIC regimen,] remains the standard of care [SOC] for patients with unresectable, stage III NSCLC.”

Further analysis of PFS by patient subgroup did not show any statistically significant benefit with durvalumab plus CRT vs CRT and placebo. Bradley explained that “...Almost all these subgroups [have HRs] less than 1, but they do not reach statistical significance. [Patients who are] female, [younger] than 65 years of age, from Europe, and have smaller tumor volumes perhaps [experience] better benefit with durvalumab [plus CRT] than other patients.”

Similar patient populations appeared to experience greater OS benefit with durvalumab plus CRT vs other subgroups, but HRs were once again not statistically significant.

Previously reported data on 5-year survival outcomes from the phase 3 PACIFIC trial (NCT02125461) showed that concurrent CRT and consolidation durvalumab led to sustained OS and PFS benefit vs placebo.² At the data cutoff date of January 11, 2021, patients treated with the durvalumab regimen achieved a 28% reduction in the risk of death with durvalumab vs placebo (stratified HR, 0.72; 95% CI, 0.59-0.89), and a 45% reduction in the risk of disease progression or death with durvalumab vs placebo (stratified HR, 0.55; 95% CI, 0.45-0.68), both of which were consistent with the primary analysis. The estimated 5-year OS rate was 42.9% with durvalumab vs 33.4% with placebo, and the estimated 5-year PFS rates were 33.1% and 19.0%, respectively.

Despite the efficacy seen with concurrent CRT in the PACIFIC trial, approximately 15% to 30% of patients are ineligible for consolidation durvalumab due to disease progression during or immediately following concurrent CRT or the development of adverse effects (AEs), such as radiation pneumonitis. Investigators hypothesized that starting an immuno-oncology (IO) regimen concurrently with CRT may induce responses and prolong benefit in patients who would progress on CRT alone.¹

“​​There’s preclinical evidence that supports using IO concurrently with CRT [because] it may have a synergistic effect [when added to] radiation therapy,” Bradley explained. “[This] could provide the opportunity for some patients to benefit during CRT and more patients to be eligible for IO, [and could] increase the rate and depth of responses, leading to improved clinical benefit.” The PACIFIC-2 study was the first phase 3 trial designed to assess the synergistic effect and efficacy of concurrent IO/CRT with subsequent IO consolidation in unresectable, stage III NSCLC, he added.

This randomized, double-blind, placebo-controlled, multicenter, international study enrolled patients with histologically or cytologically confirmed NSCLC.^1,3 Patients were required to have locally advanced, unresectable disease, an ECOG/World Health Organization performance status (PS) of 0 or 1, at least 1 measurable lesion that did not receive prior irradiation, and a life expectancy of 12 weeks or more at the time of randomization. Those who were previously exposed to, or on current treatment with radiation, investigational drugs, chemotherapy, durvalumab, and monoclonal antibodies, or others, were excluded from the study.

After screening, patients were randomly assigned 2:1 to receive a fixed 1500-mg dose of intravenous (IV) durvalumab plus CRT vs placebo plus CRT every 4 weeks at the initiation of definitive chemoradiation.¹ Those who achieved a CR, PR, or stable disease following chemoradiation continued treatment with durvalumab or placebo as consolidation therapy until the time of disease progression. Patients were stratified according to whether they were younger than 65 years of age or 65 years of age and older, and whether they had stage IIIA vs IIIB/C disease.

The trial’s primary end point was PFS by BICR as per RECIST v1.1 criteria. Key secondary end points included OS, objective response rate, OS rate at 24 months, duration of response, disease control rate, time from randomization to second progression, time to death or distant metastasis, health-related quality of life, safety, and pharmacokinetics.

A total of 328 patients were recruited onto the study across 106 sites in Asia, Eastern Europe, and the Americas. Recruitment began on March 29, 2018, and continued through June 24, 2019. Across the durvalumab and placebo arms in the ITT population, the median age of patients was 63.0 years (range, 36-84; range, 38-84), with most patients at least 50 to 65 years of age (48.9%; 45.9%). The majority of patients were male (75.8; 73.4%), White (64.4%; 56.9%), had an ECOG PS of 1 (55.3%; 51.4%) and had PD-L1 positivity (51.6%; 55.0%). Patients in the durvalumab group primarily displayed squamous histology (55.3%); those in the placebo group primarily had nonsquamous disease (52.3%).

Regarding mutational status, 51.1% and 55.0% of patients in the durvalumab vs placebo arms, respectively, had EGFR-negative disease. Most had stage IIIB disease (49.8%; 46.8%), followed by stage IIIA disease (34.7%; 33.9%), stage IIIC disease (15.1%; 18.3%), and stage IV disease (0.5%; 0.9%). Almost all patients in both groups did not have distant metastases (99.5%; 99.1%), and over half had N2 regional lymph nodes (56.6%; 55,0%). T4 primary tumors were observed in 57.5% of patients in the durvalumab group and 48.6% of those in the placebo group.

All patients in the placebo arm received CRT compared with all but 1 patient in the durvalumab arm, and 98.2% of patients across both arms underwent radiation therapy. SOC CRT included either cisplatin plus etoposide (durvalumab arm, 5.0%; placebo arm, 10.1%), carboplatin plus paclitaxel (75.8%; 74.3%), pemetrexed plus cisplatin (8.2%; 7.3%), or pemetrexed plus carboplatin (10.5%; 8.3%) according to the investigator’s discretion. Of these, 88.1% and 90.8% of patients completed CRT in the durvalumab and placebo arms, respectively. Patients discontinued CRT because of AEs (9.2%; 4.6%), disease progression (1.8%; 1.8%), patient decision (0.9%; 0.9%), or other reasons (0.0%; 1.8%)

Durvalumab was administered to 99.5% of patients in the investigative arm and placebo was given to 100% of those in the control arm. Reasons for durvalumab or placebo discontinuation at any time included AEs (83.9%; 84.4%), disease progression (26.6%; 13.8%), patient decision (53.7%; 61.5%), development of specific discontinuation criteria (0.0%; 0.9%), or other reasoning (1.4%; 1.8%).

Most AEs leading to durvalumab or placebo discontinuation (14.2%; 5.6%) occurred between 0 and 4 months, which approximately corresponds with the initiation of IO plus CRT up to the time of the first baseline scan. Remaining AEs leading to discontinuation occurred from 4 months to 16 months (5.5%; 5.6%) after treatment was started, and longer than 16 months (5.9%; 0.9%) from the start of treatment.

Toxicity and tolerability profiles for each treatment regimen were consistent with their known profiles. Any-grade AEs were observed in 98.6% of patients in the durvalumab arm and 100% of those in the placebo arm; 53.4% and 59.3% of these effects were a maximum of grade 3/4 in severity. Serious AEs were observed in 47.0% and 51.9% of patients in these respective groups, and 13.7% and 10.2% of patients experienced AEs that proved fatal.

The most common treatment-emergent AEs (TEAEs) in the durvalumab arm were anemia (42.0%), pneumonitis/radiation pneumonitis (28.8%), neutropenia (27.4%) and nausea (25.6%). In the placebo arm, the most common TEAEs constituted anemia (38.0%), constipation (28.7%), pneumonitis or radiation pneumonitis (28.7%) and neutropenia (25.9%). Combined rates of any-grade pneumonitis/radiation pneumonitis were comparable between arms, and grade 3 or greater pneumonitis/radiation pneumonitis occurred in 4.6% and 5.6% of patients in the durvalumab and placebo arms, respectively.

Bradley noted that a higher number of grade 3/4 AEs and AEs leading to death occurred during the first 4 months of treatment with durvalumab plus CRT (grade 3/4, 57.1%; leading to death, 6.8%) vs placebo (52.8%; 4.6%), adding that most AEs leading to death in the durvalumab arm were caused by infections occurring early in the treatment course (2.7%).

References

1. Bradley J, Suguwara S, Lee KH, et al. Durvalumab in combination with chemoradiotherapy for patients with unresectable stage III NSCLC: Final results from PACIFIC-2. Presented at: 2023 European Lung Cancer Congress; March 20-23, 2023; Prague, Czech Republic. Abstract LBA1.
2. Spigel DR, Faivre-Finn C, Gray JE, et al. Five-year survival outcomes from the PACIFIC trial: durvalumab after chemoradiotherapy in stage III non-small-cell lung cancer [published correction appears in J Clin Oncol. 2022 Jun 10;40(17):1965]. J Clin Oncol. 2022;40(12):1301-1311. doi:10.1200/JCO.21.01308
3. Study of durvalumab given with chemoradiation therapy in patients with unresectable non-small cell lung cancer. ClinicalTrials.gov. Updated January 12, 2024. Accessed March 22, 2024. https://clinicaltrials.gov/study/NCT03519971