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Randomized Controlled Trial
. 2024 Feb 16;30(4):824-835.
doi: 10.1158/1078-0432.CCR-23-1689.

Durvalumab ± Tremelimumab + Platinum-Etoposide in Extensive-Stage Small Cell Lung Cancer (CASPIAN): Outcomes by PD-L1 Expression and Tissue Tumor Mutational Burden

Luis Paz-Ares  1 , Marina Chiara Garassino  2   3 , Yuanbin Chen  4 , Niels Reinmuth  5 , Katsuyuki Hotta  6 , Artem Poltoratskiy  7 , Dmytro Trukhin  8 , Maximilian J Hochmair  9 , Mustafa Özgüroğlu  10 , Jun Ho Ji  11 , Galina Statsenko  12 , Nikolay Conev  13 , Igor Bondarenko  14 , Libor Havel  15 , György Losonczy  16 , Mingchao Xie  17 , Zhongwu Lai  18 , Nadia Godin-Heymann  19 , Helen Mann  19 , Haiyi Jiang  18 , Yashaswi Shrestha  18 , Jonathan W Goldman  20
Affiliations
Randomized Controlled Trial

Durvalumab ± Tremelimumab + Platinum-Etoposide in Extensive-Stage Small Cell Lung Cancer (CASPIAN): Outcomes by PD-L1 Expression and Tissue Tumor Mutational Burden

Luis Paz-Ares et al. Clin Cancer Res. .

Abstract

Purpose: 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.

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Figures

Figure 1. Subgroup analysis of OS by PD-L1 TC and IC expression for durvalumab plus tremelimumab plus EP versus EP (A) and durvalumab plus EP versus EP (B). In each panel, the shaded band shows the CI for the ITT population; circle sizes are proportional to the number of events. CI, confidence interval; D, durvalumab; EP, platinum-etoposide; HR, hazard ratio; IC, immune cell; ITT, intention-to-treat; OS, overall survival; PD-L1, programmed cell death ligand-1; T, tremelimumab; TC, tumor cell.
Figure 1.
Subgroup analysis of OS by PD-L1 TC and IC expression for durvalumab plus EP versus EP (A) and durvalumab plus tremelimumab plus EP versus EP (B). In each panel, the shaded band shows the CI for the ITT population; circle sizes are proportional to the number of events. CI, confidence interval; D, durvalumab; EP, platinum-etoposide; HR, hazard ratio; IC, immune cell; ITT, intention-to-treat; OS, overall survival; PD-L1, programmed cell death ligand-1; T, tremelimumab; TC, tumor cell.
Figure 2. Kaplan–Meier analysis of OS for the PD-L1 TC or IC ≥1% subgroup (A) and the PD-L1 TC and IC <1% subgroup (B). CI, confidence interval; D, durvalumab; EP, platinum-etoposide; HR, hazard ratio; IC, immune cell; OS, overall survival; PD-L1, programmed cell death ligand-1; T, tremelimumab; TC, tumor cell.
Figure 2.
Kaplan–Meier analysis of OS for the PD-L1 TC or IC ≥1% subgroup (A) and the PD-L1 TC and IC <1% subgroup (B). CI, confidence interval; D, durvalumab; EP, platinum-etoposide; HR, hazard ratio; IC, immune cell; OS, overall survival; PD-L1, programmed cell death ligand-1; T, tremelimumab; TC, tumor cell.
Figure 3. Kaplan–Meier analysis of OS by PD-L1 subgroup in durvalumab plus tremelimumab plus EP arm (A), durvalumab plus EP arm (B), and EP arm (C). CI, confidence interval; EP, platinum-etoposide; HR, hazard ratio; IC, immune cell; OS, overall survival; PD-L1, programmed cell death ligand-1; TC, tumor cell.
Figure 3.
Kaplan–Meier analysis of OS by PD-L1 subgroup in durvalumab plus EP arm (A), durvalumab plus tremelimumab plus EP arm (B), and EP arm (C). CI, confidence interval; EP, platinum-etoposide; HR, hazard ratio; IC, immune cell; OS, overall survival; PD-L1, programmed cell death ligand-1; TC, tumor cell.
Figure 4. Subgroup analysis of OS by tTMB for durvalumab plus tremelimumab plus EP versus EP (A) and durvalumab plus EP versus EP (B). In each panel, the shaded band shows the CI for the ITT population; circle sizes are proportional to the number of events. BEP, biomarker evaluable population; CI, confidence interval; D, durvalumab; EP, platinum-etoposide; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; mut/Mb, mutations per megabase; T, tremelimumab; tTMB, tissue tumor mutational burden.
Figure 4.
Subgroup analysis of OS by tTMB for durvalumab plus EP versus EP (A) and durvalumab plus tremelimumab plus EP versus EP (B). In each panel, the shaded band shows the CI for the ITT population; circle sizes are proportional to the number of events. BEP, biomarker evaluable population; CI, confidence interval; D, durvalumab; EP, platinum-etoposide; HR, hazard ratio; ITT, intention-to-treat; OS, overall survival; mut/Mb, mutations per megabase; T, tremelimumab; tTMB, tissue tumor mutational burden.
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