INTRODUCTION:In the first interim analysis of the phase 3 ADRIATIC trial, consolidation durvalumab significantly improved overall survival and progression-free survival (primary end points) versus placebo in patients with limited-stage SCLC without disease progression after concurrent chemoradiotherapy. We report the patient-reported outcomes. METHODS:Patients received durvalumab, durvalumab-tremelimumab, or placebo every 4 weeks for up to 24 months. Patient-reported global health status/quality of life (QoL), functioning, and symptoms, assessed using the European Organisation for Research and Treatment of Cancer QoL Questionnaire-Core 30-item and QoL Questionnaire-Lung Cancer 13-item (secondary end points), are reported for durvalumab and placebo only; the durvalumab-tremelimumab arm remained blinded at this analysis. Change from baseline (for prespecified key scales), time to deterioration (TTD), and improvement rates (all scales) were evaluated. A score change of more than or equal to 10 from baseline was considered a clinically meaningful deterioration or improvement. Analyses were not alpha controlled. RESULTS:In both arms (durvalumab, n = 264; placebo, n = 266), mean score changes in prespecified key scales from baseline up to 24 months were small and not clinically meaningful. There were no between-arm differences in TTD except for arm or shoulder pain (longer with durvalumab versus placebo [median TTD: 25.7 versus 9.1 mo; hazard ratio: 0.70 (95% confidence interval: 0.51-0.94)]) and similar improvement rates between arms for most scales; a higher improvement rate for chest pain was observed with durvalumab versus placebo (odds ratio: 2.28 [95% confidence interval: 1.08-4.95]). CONCLUSIONS:Consolidation durvalumab after concurrent chemoradiotherapy did not compromise patients' global health status/QoL, functioning, or symptoms versus placebo, further supporting this treatment regimen as the new standard of care for limited-stage SCLC.

Introduction: The phase 1 CLOVER study (NCT03509012) evaluated durvalumab with or without tremelimumab in combination with concurrent chemoradiotherapy (cCRT) in patients with advanced solid tumors; here, we report findings from the limited-stage SCLC (LS-SCLC) cohort. Methods: Patients with pathologically confirmed LS-SCLC whose disease could be encompassed within a radical radiation portal received durvalumab (arms 1 and 2) or durvalumab plus tremelimumab (arms 3 and 4) in combination with cCRT (cisplatin-etoposide and either standard radiotherapy [arms 1 and 3] or hyperfractionated radiotherapy [arms 2 and 4]). The primary end point was safety and tolerability. Preliminary efficacy and candidate biomarkers of response were assessed. Results: Overall, 33 patients were enrolled: 12 in arm 1, 12 in arm 2, six in arm 3, and three in arm 4. No patients had dose-limiting toxicity. Grade 3 or 4 adverse events occurred in 79.2% of patients from arms 1 and 2 and 88.9% from arms 3 and 4; the most common were hematologic events. In arms 1, 2, 3, and 4, objective response rate was 66.7%, 66.7%, 83.3%, and 100.0%, disease control rate was 90.9%, 100.0%, 100.0%, and 100.0% at 18 weeks and 72.7%, 83.3%, 100.0%, and 100.0% at 48 weeks, and the median progression-free survival (PFS) (95% confidence interval) was 9.2 months (5.3‒not estimable [NE]), 16.6 months (8.4–NE), not reached (16.6–NE), and 9.3 months (6.3–NE), respectively. In exploratory biomarker analyses, no difference in PFS by programmed cell death-ligand 1 expression level was observed; median PFS was numerically greater in high versus low tumor inflammation signature and CD8A expression subgroups. Conclusions: Durvalumab in combination with cCRT, with or without tremelimumab, was tolerable and active in patients with LS-SCLC.

At the first interim analysis of the global, randomized, phase 3, double-blind ADRIATIC trial in patients with limited-stage small-cell lung cancer (LS-SCLC) not progressing after concurrent chemoradiotherapy (cCRT), consolidation durvalumab significantly improved overall survival (OS; hazard ratio [HR] 0.73) and progression-free survival (PFS) by blinded independent central review (BICR; HR 0.76) versus placebo (dual primary endpoints). We report an exploratory analysis in patients enrolled in Japan. Patients received durvalumab 1500 mg (N = 264), durvalumab+tremelimumab 75 mg (4 doses, N = 200; arm remained blinded), or placebo (N = 266) every 4 weeks for ≤ 24 months. Prior cCRT ± prophylactic cranial irradiation (PCI) was per local standards of care. In the Japan subgroup, 19 and 31 patients received durvalumab and placebo, respectively; prior cCRT comprised cisplatin-etoposide/carboplatin-etoposide in 94.7/5.3% and 87.1/12.9% and once-daily/twice-daily radiotherapy in 10.5/89.5% and 0/100%; 52.6% and 58.1% received PCI. Median OS was not reached versus 44.9 months (3-year OS 67.4% versus 58.1%; HR 0.67, 95% CI 0.24-1.62). Median PFS by BICR was 44.2 versus 29.4 months (24-month PFS 59.6% vs. 58.6%; HR 1.05, 95% CI 0.44-2.36); median PFS by investigator assessment (sensitivity analysis) was 44.2 versus 19.7 months (24-month PFS 65.6% vs. 47.0%; HR 0.68, 95% CI 0.28-1.51). With durvalumab and placebo, 21.1% and 19.4% had maximum grade 3-4 adverse events (AEs), 21.1% and 9.7% had AEs leading to treatment discontinuation, and 52.6% and 45.2% had pneumonitis/radiation pneumonitis (grade 3-4: 0% and 6.5%). In conclusion, consolidation durvalumab demonstrated a favorable risk/benefit profile in Japanese patients with LS-SCLC post cCRT. Trial Registration: ClinicalTrials.gov identifier: NCT03703297.

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.

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.

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.

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

Introduction: For patients with unresectable, stage III non -small -cell lung cancer (NSCLC), current standard of care is concurrent chemoradiotherapy (cCRT) followed by consolidation durvalumab. However, earlier initiation of durvalumab simultaneously with cCRT may increase antitumor activity relative to initiation after cCRT. The phase 1 CLOVER study (NCT03509012) evaluated durvalumab combined with cCRT in patients with advanced solid tumors; we report findings from the NSCLC cohort. Methods: CLOVER comprised a dose -limiting toxicity (DLT) assessment part, followed by an expansion part. In the NSCLC cohort, patients with previously untreated, unresectable, stage III NSCLC were enrolled in three treatment arms: durvalumab every 4 weeks (Q4W) + cisplatin + etoposide + radiotherapy (Arm 1); durvalumab Q4W + carboplatin + paclitaxel + radiotherapy (Arm 2); or durvalumab Q4W + carboplatin or cisplatin + pemetrexed + radiotherapy (non-squamous histology only; Arm 3). Patients received durvalumab until disease progression or unacceptable toxicity. The primary endpoint was safety and tolerability. Results: Sixty-four patients were enrolled: 21, 22, and 21 in Arms 1, 2, and 3, respectively. One patient in Arm 1 had DLT (grade 3 aspartate aminotransferase increase and grade 4 alanine aminotransferase increase); no DLTs were observed in Arms 2 or 3. Grade 3/4 adverse events occurred in 76.6 % of patients overall; the most common were neutropenia (51.6 %), leukopenia (20.3 %), and anemia (17.2 %). In a post -hoc analysis, 7.8 % of patients had grade 3 pneumonitis/radiation pneumonitis (grouped term) events. Overall, the objective response rate was 60.9 % (95 % confidence interval [CI], 47.9-72.9); median duration of response was 15.8 months (95 % CI, 9.0-not estimable [NE]). Median progression -free survival was 13.4 months (95 % CI, 8.8-20.1) and median overall survival was not reached (95 % CI, 21.9-NE). Conclusion: Durvalumab in combination with cCRT was well tolerated, with a manageable safety profile and showed encouraging antitumor activity in patients with unresectable, stage III NSCLC.

LBA5 Background: The standard of care (SoC) for pts with LS-SCLC is concurrent platinum-based chemoradiotherapy (cCRT) ± prophylactic cranial irradiation (PCI). ADRIATIC (NCT03703297), a phase 3, randomized, double-blind, placebo (PBO)-controlled, multicenter, global study, assessed D ± tremelimumab (T) as consolidation tx for pts with LS-SCLC who had not progressed after cCRT. Here we report results for D vs PBO from the first planned interim analysis (IA). Methods: Eligible pts had stage I–III LS-SCLC (stage I/II inoperable) and WHO performance status 0/1, and had not progressed after cCRT. PCI was permitted before randomization. Pts were randomized 1–42 days after cCRT to D 1500 mg + PBO, D 1500 mg + T 75 mg, or PBO + PBO every 4 weeks (Q4W) for 4 cycles, followed by D (D±T arms) or PBO Q4W until investigator-determined progression or intolerable toxicity, or for a maximum of 24 months (mo). The first 600 pts were randomized in a 1:1:1 ratio; subsequent pts were randomly assigned 1:1 to D or PBO. Randomization was stratified by stage (I/II vs III) and receipt of PCI (yes vs no). The dual primary endpoints were OS and PFS (blinded independent central review per RECIST v1.1) for D vs PBO. OS and PFS for D+T vs PBO were alpha-controlled secondary endpoints. Results: 730 pts were randomized, including 264 to D and 266 to PBO. Baseline characteristics and prior tx were well balanced between arms. Radiation schedule in the D vs PBO arms was once daily in 73.9% vs 70.3% of pts and twice daily in 26.1% vs 29.7%; 53.8% of pts in each arm received PCI. At this IA (data cutoff 15Jan2024), median (range) duration of follow-up for OS and PFS in censored pts was 37.2 (0.1–60.9) and 27.6 (0.0–55.8) mo, respectively. OS was significantly improved with D vs PBO (HR 0.73 [95% CI 0.57–0.93]; p=0.0104; median OS 55.9 [95% CI 37.3 – not estimable] vs 33.4 [25.5–39.9] mo; 24-mo OS rate 68.0% vs 58.5%; 36-mo OS rate 56.5% vs 47.6%). PFS was also significantly improved with D vs PBO (HR 0.76 [95% CI 0.61–0.95]; p=0.0161; median PFS 16.6 [95% CI 10.2–28.2] vs 9.2 [7.4–12.9] mo; 18-mo PFS rate 48.8% vs 36.1%; 24-mo PFS rate 46.2% vs 34.2%). Tx benefit was generally consistent across predefined pt subgroups for both OS and PFS. With D vs PBO, maximum grade 3/4 all-cause adverse events (AEs) occurred in 24.3% vs 24.2% of pts; AEs led to tx discontinuation in 16.3% vs 10.6% of pts and to death in 2.7% vs 1.9%. Any-grade pneumonitis/radiation pneumonitis was reported in 38.0% vs 30.2% of pts with D vs PBO (maximum grade 3/4 in 3.0% vs 2.6%). The D+T arm remains blinded until the next planned analysis. Conclusions: D as consolidation tx after cCRT demonstrated a statistically significant and clinically meaningful improvement in OS and PFS compared with PBO in pts with LS-SCLC. D was well tolerated and AEs were consistent with the known safety profile, with no new signals observed. These data support consolidation D as a new SoC for pts with LS-SCLC who have not progressed after cCRT. Clinical trial information: NCT03703297 .

Abstract Background We explored potential predictive biomarkers of immunotherapy response in patients with extensive-stage small-cell lung cancer (ES-SCLC) treated with durvalumab (D) + tremelimumab (T) + etoposide-platinum (EP), D + EP, or EP in the randomized phase 3 CASPIAN trial. Methods 805 treatment-naïve patients with ES-SCLC were randomized (1:1:1) to receive D + T + EP, D + EP, or EP. The primary endpoint was overall survival (OS). Patients were required to provide an archived tumor tissue block (or ≥ 15 newly cut unstained slides) at screening, if these samples existed. After assessment for programmed cell death ligand-1 expression and tissue tumor mutational burden, residual tissue was used for additional molecular profiling including by RNA sequencing and immunohistochemistry. Results In 182 patients with transcriptional molecular subtyping, OS with D ± T + EP was numerically highest in the SCLC-inflamed subtype (n = 10, median 24.0 months). Patients derived benefit from immunotherapy across subtypes; thus, additional biomarkers were investigated. OS benefit with D ± T + EP versus EP was greater with high versus low CD8A expression/CD8 cell density by immunohistochemistry, but with no additional benefit with D + T + EP versus D + EP. OS benefit with D + T + EP versus D + EP was associated with high expression of CD4 (median 25.9 vs. 11.4 months) and antigen-presenting and processing machinery (25.9 vs. 14.6 months) and MHC I and II (23.6 vs. 17.3 months) gene signatures, and with higher MHC I expression by immunohistochemistry. Conclusions These findings demonstrate the tumor microenvironment is important in mediating better outcomes with D ± T + EP in ES-SCLC, with canonical immune markers associated with hypothesized immunotherapy mechanisms of action defining patient subsets that respond to D ± T. Trial registration ClinicalTrials.gov, NCT03043872.

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

Abstract Purpose: The phase II, multiarm, signal-searching BALTIC study (NCT02937818) assessed novel treatment combinations for platinum-refractory/resistant extensive-stage small cell lung cancer (ES-SCLC). Patients and Methods: Patients with ES-SCLC with progressive disease during or within 90 days of completing first-line platinum-based chemotherapy received one of three regimens: durvalumab plus tremelimumab followed by durvalumab monotherapy (arm A), adavosertib plus carboplatin (arm B), or ceralasertib plus olaparib (arm C). The primary endpoint was the objective response rate. Prespecified exploratory biomarker analyses were conducted in arms A and C. Results: In arm A (n = 41), arm B (n = 10), and arm C (n = 21), the confirmed objective response rates were 7.3%, 0%, and 4.8%, respectively. Safety profiles in all arms were consistent with those of the individual drugs. In arm A, patients with PD-L1 expression (tumor cells or immune cells) ≥1% seemed to have a greater likelihood of achieving disease control with durvalumab plus tremelimumab than those with PD-L1 (tumor cells and immune cells) <1%, and lower baseline ctDNA and reduction in the on-treatment ctDNA level were both associated with longer overall survival. Among patients treated with ceralasertib plus olaparib in arm C, specific immune response-relevant circulating chemokines and cytokines were identified as early biomarkers of survival and pharmacodynamic biomarkers. Conclusions: In BALTIC, all combination regimens demonstrated tolerable safety profiles, but antitumor activity was limited in refractory/resistant ES-SCLC. Among patients treated with durvalumab plus tremelimumab, an association of on-treatment reduction in ctDNA with longer overall survival suggests the potential use of ctDNA as a surrogate of treatment response, warranting further investigation.

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.

Treatment exposure by PD-L1 subgroup (PD-L1 safety population).

Prevalence of PD-L1 expression on TC and IC in the PD-L1 BEP. *Includes patients whose tumors had <1% PD-L1 expression on TCs or ICs, but not absolute zero.

Relationship between PD-L1 expression and tTMB score. (A) Box plots showing the distribution of tTMB score in patients by PD-L1 subgroup; (B) Venn diagram showing overlap between the tTMB ≥10 mut/Mb and PD-L1 TC or IC ≥1% subgroups. Percentages are calculated from the PD-L1 and tTMB BEP, i.e., patients who had both a PD-L1 and a tTMB result (n=275); samples from 171 patients had tTMB ≥10 mut/Mb and/or PD-L1 TC or IC ≥1%, while samples from 104 patients (37.8%) had both tTMB <10 mut/Mb and PD-L1 TC and IC <1%.

Introduction: In the phase 3 study involving the use of durvalumab with or without tremelimumab in combination with platinum-based chemotherapy in untreated extensive -stage SCLC (CASPIAN study), first-line durvalumab plus platinum-etoposide (EP) significantly improved overall survival (OS) versus EP alone (p = 0.0047). We report exploratory subgroup analyses of treatment patterns and outcomes according to the presence of baseline brain or central nervous system metastases.Methods: Patients (WHO performance status 0 or 1), including those with asymptomatic or treated-and-stable brain metastases, were randomized to four cycles of dur-valumab plus EP followed by maintenance durvalumab until progression or up to six cycles of EP and optional prophy-lactic cranial irradiation. Prespecified analyses of OS and progression-free survival (PFS) in subgroups with or without brain metastases used unstratified-Cox proportional hazards models. The data cutoff was on January 27, 2020.Results: At baseline, 28 out of 268 patients (10.4%) in the durvalumab plus EP arm and 27 out of 269 patients (10.0%) in the EP arm had known brain metastases, of whom 3 of 28 (10.7%) and 4 of 27 (14.8%) had previous brain radio-therapy, respectively. Durvalumab plus EP (versus EP alone) prolonged OS (hazard ratio, 95% confidence interval) in patients with (0.79, 0.44-1.41) or without (0.76, 0.62-0.92) brain metastases, with similar PFS results (0.73, 0.42-1.29 and 0.80, 0.66-0.97, respectively). Among patients without brain metastases, similar proportions in each arm developed new brain lesions as part of their first progression (8.8% and 9.5%), although 8.3% in the EP arm received prophy-lactic cranial irradiation. Similar proportions in each arm received subsequent brain radiotherapy (20.5% and 21.2%), although more common in patients with than without baseline brain metastases (45.5% and 18.0%).Conclusions: The OS and PFS benefit with first-line durvalumab plus EP were maintained irrespective of the presence of brain metastases, further supporting its standard-of-care use.(c) 2022 The Authors. Published by Elsevier Inc. on behalf of the International Association for the Study of Lung Cancer. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/ 4.0/).