INTRODUCTION:In the phase 3 CASPIAN study, first-line durvalumab plus etoposide combined with either carboplatin or cisplatin (EP) significantly improved overall survival (OS) versus EP alone in treatment-naïve extensive-stage small-cell lung cancer (ES-SCLC). We report exploratory subgroup analyses from CASPIAN. METHODS:Patients with untreated ES-SCLC were randomized to durvalumab plus EP or EP alone. We analyzed OS and safety in subgroups defined by age, sex, and planned platinum agent, and patient-reported outcomes (PROs) by age. RESULTS:Of 537 patients (durvalumab plus EP: n = 268; EP alone: n = 269), 80.6% versus 19.4% were aged <70 versus ≥70 years; 69.6% versus 30.4% were male versus female; and planned platinum was cisplatin versus carboplatin in 25.1% versus 74.9%. The OS HRs for durvalumab plus EP versus EP were 0.71 (95% CI, 0.58-0.88) versus 0.74 (95% CI, 0.49-1.11) for patients aged <70 versus ≥70 years; 0.76 (95% CI, 0.62-0.95) versus 0.60 (95% CI, 0.42-0.84) for males versus females; and 0.65 (95% CI, 0.45-0.94) versus 0.74 (95% CI, 0.60-0.91) for planned cisplatin versus carboplatin. With durvalumab plus EP, rates of grade 3/4 adverse events (AEs) were similar across subgroups; serious AEs were more frequent in patients aged ≥70 versus <70 years; and immune-mediated AEs were more common in females versus males. Adding durvalumab to EP had no detrimental effect on PROs in either age subgroup. CONCLUSIONS:These findings support the use of durvalumab plus EP as first-line standard of care for ES-SCLC. Additional trials focused on elderly populations would be informative.

INTRODUCTION:The primary analysis (median follow-up 34.9 mo across all arms) of the phase 3 POSEIDON study revealed a statistically significant overall survival (OS) improvement with first-line tremelimumab plus durvalumab and chemotherapy (T+D+CT) versus CT in patients with EGFR and ALK wild-type metastatic NSCLC (mNSCLC). D+CT had a trend for OS improvement versus CT that did not reach statistical significance. This article reports prespecified OS analyses after long-term follow-up (median >5 y). METHODS:A total of 1013 patients were randomized (1:1:1) to T+D+CT, D+CT, or CT, stratified by tumor cell programmed cell death ligand-1 (PD-L1) expression (≥50% versus <50%), disease stage (IVA versus IVB), and tumor histologic type (squamous versus nonsquamous). Serious adverse events were collected during follow-up. RESULTS:After a median follow-up of 63.4 months across all arms, T+D+CT had sustained OS benefit versus CT (hazard ratio [HR] = 0.76, 95% confidence interval [CI]: 0.64-0.89; 5-y OS: 15.7% versus 6.8%). OS improvement with D+CT versus CT (HR = 0.84, 95% CI: 0.72-1.00; 5-y OS: 13.0%) was consistent with the primary analysis. OS benefit with T+D+CT versus CT remained more pronounced in nonsquamous (HR = 0.69, 95% CI: 0.56-0.85) versus squamous (HR = 0.85, 95% CI: 0.65-1.10) mNSCLC. OS benefit with T+D+CT versus CT was still evident regardless of PD-L1 expression, including patients with PD-L1 tumor cell less than 1%, and remained evident in STK11-mutant (nonsquamous), KEAP1-mutant, and KRAS-mutant (nonsquamous) mNSCLC. No new safety signals were identified. CONCLUSIONS:After a median follow-up of more than 5 years, T+D+CT had durable long-term OS benefit versus CT, supporting its use as first-line treatment in mNSCLC, including in patient subgroups with harder-to-treat disease.

INTRODUCTION:PEARL (NCT03003962) is an open-label, phase 3 study comparing first-line durvalumab monotherapy with chemotherapy in patients with metastatic NSCLC (mNSCLC [EGFR/ALK wild type]) with programmed cell death ligand 1 (PD-L1) tumor cell (TC) membrane expression status of 25% or higher. We report the final analysis of PEARL. METHODS:Adults (N = 669) with previously untreated stage IV mNSCLC were randomized (1:1) to durvalumab 20 mg/kg every four weeks or chemotherapy every three weeks for four to six cycles. The dual primary endpoints were overall survival (OS) in the population with PD-L1 TC of 25% or higher and OS in the population at low risk of early mortality (LREM) with PD-L1 TC of 25% or higher. RESULTS:Durvalumab was associated with a numerical reduction in the risk of death versus chemotherapy in the 25% and higher PD-L1 TC population (OS hazard ratio [HR] = 0.84, 95% confidence interval [CI]: 0.71-0.99, p = 0.037; median OS 14.6 months, 95% CI: 12.2-16.9 versus 12.8 months, 95% CI: 10.1-14.7, respectively). In the 25% and higher PD-L1 TC low risk of early mortality population the OS hazard ratio for durvalumab versus chemotherapy was 0.96 (95% CI: 0.79-1.15, p = 0.628); median OS 14.6 months (95% CI: 12.6-17.2) versus 15.0 months (95% CI: 13.1-16.8), respectively. In the safety population, the incidence of grade 3 or 4 treatment-related adverse events was 15.5% (durvalumab) and 45.9% (chemotherapy). CONCLUSIONS:Durvalumab did not statistically significantly improve OS versus chemotherapy as first-line treatment in patients with mNSCLC and 25% and higher PD-L1 TC. The numerical improvement in OS was consistent with previous studies of first-line immune checkpoint inhibitor monotherapy in patients with mNSCLC.

Subgroup analysis of PFS by tTMB for (A) durvalumab plus tremelimumab plus EP versus EP and (B) durvalumab plus EP versus EP. In each panel, the shaded band shows the confidence interval for the ITT population; circle sizes are proportional to the number of events.

LBA246 Background: FLOT was established as a perioperative therapy for GC/GEJC following the Phase 2/3 FLOT4 study conducted in Germany, with a pCR rate of 16% (Al-Batran et al, Lancet Oncol 2016). The global MATTERHORN study (NCT04592913) showed a statistically significant improvement in pCR with perioperative D + FLOT vs placebo (P) + FLOT in GC/GEJC at first interim analysis (Janjigian et al, ESMO Congress 2023). Subgroup analyses by region and country were completed to assess pCR rates with FLOT and benefit of D + FLOT across the global study population. Methods: Participants (pts) with resectable GC/GEJC were randomized 1:1 to D 1500 mg or P every 4 weeks (Q4W) on Day 1 plus FLOT Q2W on Days 1 and 15 for 4 cycles (2 doses of D or P and 4 doses of FLOT pre- and post-operative), followed by D 1500 mg or P on Day 1 Q4W for 10 further cycles. Randomization was stratified by Asia vs non-Asia. pCR (Modified Ryan; central review) was assessed in prespecified (Asia) and post hoc regional subgroups, including 6 countries with the highest numbers of randomized pts. Results: Of 948 pts randomized globally, 180 pts (19%) were in Asia. pCR outcomes with FLOT in Asia were consistent with the global outcomes. pCR rates were improved with D + FLOT vs P + FLOT in all regions (Asia, Europe, North America and South America; Table), despite some imbalances in baseline characteristics and numerical differences in pCR rates by geographic location. The pCR rate with P + FLOT in the German subgroup (13%; 95% CI, 6.1–23.0) was similar to that with FLOT in the FLOT4 study. Improvement in pCR with D + FLOT vs P + FLOT was observed across subgroups by country. Similar trends across regional subgroups were observed for combined complete and near-complete response rate. Conclusions: In MATTERHORN, pCR was consistently improved with the addition of D to perioperative FLOT in GC/GEJC across geographic regions. The study is ongoing for the primary objective of event-free survival. Clinical trial information: NCT04592913 .[Table: see text]

Baseline patient demographics and disease characteristics for the PD-L1 and tTMB BEPs and the ITT population.

Summary of adverse events of any cause in the PD-L1, tTMB, and overall safety populations.

8011 Background: In the phase 3 AEGEAN study (NCT03800134), perioperative D + neoadj chemotherapy (CT) vs neoadj CT alone significantly improved the primary EPs of event-free survival (EFS) and pathological complete response (pCR; absence of residual viable tumor [RVT] in resection specimen, incl. primary tumor and sampled lymph nodes) with manageable safety in pts with R-NSCLC (modified ITT [mITT] population). Here, we report exploratory analyses of pts in AEGEAN with baseline N2 nodal status. Methods: Pts with Tx-naïve R-NSCLC (stage II–IIIB[N2]; AJCC 8th ed) were randomized (1:1) to 4 cycles of platinum-based CT plus D 1500 mg IV or placebo (PBO) Q3W before surgery (Sx), followed by D or PBO (Q4W, 12 cycles) after Sx. The mITT population excluded pts with known EGFR/ ALK alterations. Efficacy was assessed in an mITT subpopulation with baseline N2 nodal status (per investigator). Safety was assessed in all N2 R-NSCLC pts who had ≥1 Tx dose. Results: Of 740 pts in the mITT population, 366 (49.5%) had baseline N2 nodal status (D, n = 181; PBO, n = 185). In the N2 subgroup, 83.4% in the D arm and 84.9% in the PBO arm completed 4 cycles of platinum-doublet CT; 77.9% and 77.8%, respectively, had Sx; and 73.5% and 71.9% completed Sx. In the N2 subgroup, similar to the overall mITT population, EFS was prolonged in the D vs PBO arm (HR, 0.63 [95% CI: 0.43–0.90]); rates of pCR (16.6% vs 4.9%; difference, 11.7% [95% CI: 5.6–18.4]) and major pathological response (MPR, ≤10% RVT in primary tumor; 32.6% vs 15.1%; difference, 17.5% [95% CI: 8.8–26.0]) were higher in the D vs PBO arm. While EFS benefit in the D vs PBO arm was similar among pts with single- (HR, 0.61 [95% CI: 0.39–0.94]) or multi-station N2 (HR, 0.69 [95% CI: 0.33–1.38]), pCR benefit was less pronounced in multi-station pts (difference in pCR rate, 13.9% [95% CI: 6.6–21.7] for single-station N2 vs 3.8% [95% CI: –9.2–18.8] for multi-station N2). Among pts in the N2 subgroup who had Sx, similar proportions in the D and PBO arms had open (47.5% vs 50.0%) and minimally invasive procedures (50.4% vs 46.5%); 9.2% vs 11.1% had pneumonectomy (9.2% vs 9.6% in the overall mITT population). Of pts in the N2 subgroup who completed Sx, the proportion with R0 resection in the D vs PBO arm (94.7% vs 91.7%) was similar to that in the overall mITT population. Sx was delayed in a similar proportion who had Sx in the D vs PBO arm (19.9% vs 23.6%, respectively), most commonly for logistical reasons (e.g., scheduling issues). Among 394 pts who received Tx (N2 safety analysis subset; D, n = 200; PBO, n = 194), max grade 3/4 any-cause AEs occurred in 38.5% vs 41.8% in the D and PBO arm, respectively, similar to rates in the overall safety analysis set. Conclusions: With clinically meaningful improvement in efficacy, no adverse impact on Sx outcomes and a manageable safety profile, the addition of perioperative D to neoadj CT remains a potential new Tx option for pts with N2 R-NSCLC. Clinical trial information: NCT03800134 .

AbstractPurpose: In the CASPIAN trial, first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small cell lung cancer (ES-SCLC). We report exploratory analyses of CASPIAN outcomes by programmed cell death ligand-1 (PD-L1) expression and tissue tumor mutational burden (tTMB). Experimental Design: Patients were randomized (1:1:1) to durvalumab (1,500 mg) plus EP, durvalumab plus tremelimumab (75 mg) plus EP, or EP alone. Treatment effects in PD-L1 and tTMB subgroups were estimated using an unstratified Cox proportional hazards model. Results: The PD-L1 and tTMB biomarker-evaluable populations (BEP) comprised 54.4% (438/805) and 35.2% (283/805) of the intention-to-treat population, respectively. PD-L1 prevalence was low: 5.7%, 25.8%, and 28.3% had PD-L1 expression on ≥1% tumor cells (TC), ≥1% immune cells (IC), and ≥1% TCs or ICs, respectively. OS benefit with durvalumab plus EP versus EP was similar across PD-L1 subgroups, with HRs all falling within the 95% confidence interval (CI) for the PD-L1 BEP (0.47‒0.79). OS benefit with durvalumab plus tremelimumab plus EP versus EP was greater in PD-L1 ≥1% versus <1% subgroups, although CIs overlapped. There was no evidence of an interaction between tTMB and treatment effect on OS (durvalumab plus EP vs. EP, P = 0.916; durvalumab plus tremelimumab plus EP vs. EP, P = 0.672). Conclusions: OS benefit with first-line durvalumab plus EP in patients with ES-SCLC was observed regardless of PD-L1 or tTMB status. PD-L1 expression may prove to be a useful biomarker for combined treatment with PD-(L)1 and CTLA-4 inhibition, although this requires confirmation with an independent dataset. See related commentary by Rolfo and Russo, p. 652

For patients with advanced non-small-cell lung cancer (NSCLC), dual immune checkpoint blockade (ICB) with CTLA4 inhibitors and PD-1 or PD-L1 inhibitors (hereafter, PD-(L)1 inhibitors) is associated with higher rates of anti-tumour activity and immune-related toxicities, when compared with treatment with PD-(L)1 inhibitors alone. However, there are currently no validated biomarkers to identify which patients will benefit from dual ICB1,2. Here we show that patients with NSCLC who have mutations in the STK11 and/or KEAP1 tumour suppressor genes derived clinical benefit from dual ICB with the PD-L1 inhibitor durvalumab and the CTLA4 inhibitor tremelimumab, but not from durvalumab alone, when added to chemotherapy in the randomized phase III POSEIDON trial(3). Unbiased genetic screens identified loss of both of these tumour suppressor genes as independent drivers of resistance to PD-(L)1 inhibition, and showed that loss of Keap1 was the strongest genomic predictor of dual ICB efficacy-a finding that was confirmed in several mouse models of Kras-driven NSCLC. In both mouse models and patients, KEAP1 and STK11 alterations were associated with an adverse tumour microenvironment, which was characterized by a preponderance of suppressive myeloid cells and the depletion of CD8(+) cytotoxic T cells, but relative sparing of CD4(+) effector subsets. Dual ICB potently engaged CD4(+) effector cells and reprogrammed the tumour myeloid cell compartment towards inducible nitric oxide synthase (iNOS)-expressing tumoricidal phenotypes that-together with CD4(+) and CD8(+) T cells-contributed to anti-tumour efficacy. These data support the use of chemo-immunotherapy with dual ICB to mitigate resistance to PD-(L)1 inhibition in patients with NSCLC who have STK11 and/or KEAP1 alterations.

Distribution of tTMB scores by treatment arm in the tTMB BEP.

Background Adjuvant therapy with durvalumab, with or without tremelimumab, may have efficacy in patients with limited-stage small-cell lung cancer who do not have disease progression after standard concurrent platinum-based chemoradiotherapy.Methods In a phase 3, double-blind, randomized, placebo-controlled trial, we assigned patients to receive durvalumab at a dose of 1500 mg, durvalumab (1500 mg) plus tremelimumab at a dose of 75 mg (four doses only), or placebo every 4 weeks for up to 24 months. Randomization was stratified according to disease stage (I or II vs. III) and receipt of prophylactic cranial irradiation (yes vs. no). Results of the first planned interim analysis of the two primary end points of overall survival and progression-free survival (assessed on the basis of blinded independent central review according to the Response Evaluation Criteria in Solid Tumors, version 1.1) with durvalumab as compared with placebo (data cutoff date, January 15, 2024) are reported; results in the durvalumab-tremelimumab group remain blinded.Results A total of 264 patients were assigned to the durvalumab group, 200 to the durvalumab-tremelimumab group, and 266 to the placebo group. Durvalumab therapy led to significantly longer overall survival than placebo (median, 55.9 months [95% confidence interval {CI}, 37.3 to not reached] vs. 33.4 months [95% CI, 25.5 to 39.9]; hazard ratio for death, 0.73; 98.321% CI, 0.54 to 0.98; P=0.01), as well as to significantly longer progression-free survival (median 16.6 months [95% CI, 10.2 to 28.2] vs. 9.2 months [95% CI, 7.4 to 12.9]; hazard ratio for progression or death, 0.76; 97.195% CI, 0.59 to 0.98; P=0.02). The incidence of adverse events with a maximum grade of 3 or 4 was 24.4% among patients receiving durvalumab and 24.2% among patients receiving placebo; adverse events led to discontinuation in 16.4% and 10.6% of the patients, respectively, and led to death in 2.7% and 1.9%. Pneumonitis or radiation pneumonitis with a maximum grade of 3 or 4 occurred in 3.1% of the patients in the durvalumab group and in 2.6% of those in the placebo group.Conclusions Adjuvant therapy with durvalumab led to significantly longer overall survival and progression-free survival than placebo among patients with limited-stage small-cell lung cancer. (Funded by AstraZeneca; ADRIATIC ClinicalTrials.gov number, NCT03703297.) Among patients with limited-stage small-cell lung cancer, overall and progression-free survival were significantly longer with durvalumab adjuvant therapy added to standard concurrent chemoradiotherapy.

Representativeness of study participants.