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.

• MeSH
• antigeny CD274 genetika   MeSH
• etoposid MeSH
• humanizované monoklonální protilátky * MeSH
• lidé MeSH
• malobuněčný karcinom plic * farmakoterapie   genetika   MeSH
• monoklonální protilátky * MeSH
• nádory plic * farmakoterapie   genetika   MeSH
• platina MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• antigeny CD274 MeSH
• durvalumab MeSH Prohlížeč
• etoposid MeSH
• humanizované monoklonální protilátky * MeSH
• monoklonální protilátky * MeSH
• platina MeSH
• tremelimumab MeSH Prohlížeč

BACKGROUND: In the phase III CASPIAN study, first-line durvalumab in combination with etoposide plus either cisplatin or carboplatin (EP) significantly improved overall survival (OS) versus EP alone in extensive-stage small-cell lung cancer (ES-SCLC). Durvalumab plus tremelimumab plus EP numerically improved OS versus EP, but did not reach statistical significance. Here we report updated OS in censored patients after median follow-up of >3 years. PATIENTS AND METHODS: 805 patients with treatment-naïve ES-SCLC were randomized 1 : 1 : 1 to durvalumab plus EP, durvalumab plus tremelimumab plus EP, or EP. The two primary endpoints were OS for durvalumab plus EP versus EP and for durvalumab plus tremelimumab plus EP versus EP. RESULTS: As of 22 March 2021 (median follow-up 39.4 months, 86% maturity), durvalumab plus EP continued to demonstrate improved OS versus EP: hazard ratio (HR) 0.71 [95% confidence interval (CI) 0.60-0.86; nominal P = 0.0003]; median OS was 12.9 versus 10.5 months, and 36-month OS rate was 17.6% versus 5.8%. Durvalumab plus tremelimumab plus EP continued to numerically improve OS versus EP: HR 0.81 (95% CI: 0.67-0.97; nominal P = 0.0200); median OS was 10.4 months, and 36-month OS rate was 15.3%. Twenty-seven and nineteen patients in the durvalumab plus EP and durvalumab plus tremelimumab plus EP arms, respectively, remained on durvalumab treatment at data cut-off. CONCLUSIONS: Three times more patients were estimated to be alive at 3 years when treated with durvalumab plus EP versus EP, with the majority still receiving durvalumab at data cut-off, further establishing durvalumab plus EP as first-line standard of care for ES-SCLC.

• Klíčová slova
• CASPIAN, durvalumab, extensive-stage SCLC, overall survival, tremelimumab,
• MeSH
• etoposid terapeutické užití   MeSH
• humanizované monoklonální protilátky MeSH
• lidé MeSH
• malobuněčný karcinom plic * farmakoterapie   MeSH
• monoklonální protilátky MeSH
• nádory plic * farmakoterapie   MeSH
• platina terapeutické užití   MeSH
• protokoly protinádorové kombinované chemoterapie farmakologie   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• durvalumab MeSH Prohlížeč
• etoposid MeSH
• humanizované monoklonální protilátky MeSH
• monoklonální protilátky MeSH
• platina MeSH
• tremelimumab MeSH Prohlížeč

BACKGROUND: First-line durvalumab plus etoposide with either cisplatin or carboplatin (platinum-etoposide) showed a significant improvement in overall survival versus platinum-etoposide alone in patients with extensive-stage small-cell lung cancer (ES-SCLC) in the CASPIAN study. Here we report updated results, including the primary analysis for overall survival with durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide alone. METHODS: CASPIAN is an ongoing, open-label, sponsor-blind, randomised, controlled phase 3 trial at 209 cancer treatment centres in 23 countries worldwide. Eligible patients were aged 18 years or older (20 years in Japan) and had treatment-naive, histologically or cytologically documented ES-SCLC, with a WHO performance status of 0 or 1. Patients were randomly assigned (1:1:1) in blocks of six, stratified by planned platinum, using an interactive voice-response or web-response system to receive intravenous durvalumab plus tremelimumab plus platinum-etoposide, durvalumab plus platinum-etoposide, or platinum-etoposide alone. In all groups, patients received etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL/min or cisplatin 75-80 mg/m2 on day 1 of each cycle. Patients in the platinum-etoposide group received up to six cycles of platinum-etoposide every 3 weeks and optional prophylactic cranial irradiation (investigator's discretion). Patients in the immunotherapy groups received four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks. The two primary endpoints were overall survival for durvalumab plus platinum-etoposide versus platinum-etoposide and for durvalumab plus tremelimumab plus platinum-etoposide versus platinum-etoposide in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered at ClinicalTrials.gov, NCT03043872. FINDINGS: Between March 27, 2017, and May 29, 2018, 972 patients were screened and 805 were randomly assigned (268 to durvalumab plus tremelimumab plus platinum-etoposide, 268 to durvalumab plus platinum-etoposide, and 269 to platinum-etoposide). As of Jan 27, 2020, the median follow-up was 25·1 months (IQR 22·3-27·9). Durvalumab plus tremelimumab plus platinum-etoposide was not associated with a significant improvement in overall survival versus platinum-etoposide (hazard ratio [HR] 0·82 [95% CI 0·68-1·00]; p=0·045); median overall survival was 10·4 months (95% CI 9·6-12·0) versus 10·5 months (9·3-11·2). Durvalumab plus platinum-etoposide showed sustained improvement in overall survival versus platinum-etoposide (HR 0·75 [95% CI 0·62-0·91]; nominal p=0·0032); median overall survival was 12·9 months (95% CI 11·3-14·7) versus 10·5 months (9·3-11·2). The most common any-cause grade 3 or worse adverse events were neutropenia (85 [32%] of 266 patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 64 [24%] of 265 patients in the durvalumab plus platinum-etoposide group, and 88 [33%] of 266 patients in the platinum-etoposide group) and anaemia (34 [13%], 24 [9%], and 48 [18%]). Any-cause serious adverse events were reported in 121 (45%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group, 85 (32%) in the durvalumab plus platinum-etoposide group, and 97 (36%) in the platinum-etoposide group. Treatment-related deaths occurred in 12 (5%) patients in the durvalumab plus tremelimumab plus platinum-etoposide group (death, febrile neutropenia, and pulmonary embolism [n=2 each]; enterocolitis, general physical health deterioration and multiple organ dysfunction syndrome, pneumonia, pneumonitis and hepatitis, respiratory failure, and sudden death [n=1 each]), six (2%) patients in the durvalumab plus platinum-etoposide group (cardiac arrest, dehydration, hepatotoxicity, interstitial lung disease, pancytopenia, and sepsis [n=1 each]), and two (1%) in the platinum-etoposide group (pancytopenia and thrombocytopenia [n=1 each]). INTERPRETATION: First-line durvalumab plus platinum-etoposide showed sustained overall survival improvement versus platinum-etoposide but the addition of tremelimumab to durvalumab plus platinum-etoposide did not significantly improve outcomes versus platinum-etoposide. These results support the use of durvalumab plus platinum-etoposide as a new standard of care for the first-line treatment of ES-SCLC. FUNDING: AstraZeneca.

• MeSH
• časové faktory MeSH
• cisplatina aplikace a dávkování   škodlivé účinky   MeSH
• doba přežití bez progrese choroby MeSH
• etoposid aplikace a dávkování   škodlivé účinky   MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• karboplatina aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malobuněčný karcinom plic farmakoterapie   mortalita   patologie   MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• nádory plic farmakoterapie   mortalita   patologie   MeSH
• progrese nemoci MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• srovnávací studie MeSH
• Názvy látek
• cisplatina MeSH
• durvalumab MeSH Prohlížeč
• etoposid MeSH
• humanizované monoklonální protilátky MeSH
• karboplatina MeSH
• monoklonální protilátky MeSH
• tremelimumab MeSH Prohlížeč

BACKGROUND: Most patients with small-cell lung cancer (SCLC) have extensive-stage disease at presentation, and prognosis remains poor. Recently, immunotherapy has demonstrated clinical activity in extensive-stage SCLC (ES-SCLC). The CASPIAN trial assessed durvalumab, with or without tremelimumab, in combination with etoposide plus either cisplatin or carboplatin (platinum-etoposide) in treatment-naive patients with ES-SCLC. METHODS: This randomised, open-label, phase 3 trial was done at 209 sites across 23 countries. Eligible patients were adults with untreated ES-SCLC, with WHO performance status 0 or 1 and measurable disease as per Response Evaluation Criteria in Solid Tumors, version 1.1. Patients were randomly assigned (in a 1:1:1 ratio) to durvalumab plus platinum-etoposide; durvalumab plus tremelimumab plus platinum-etoposide; or platinum-etoposide alone. All drugs were administered intravenously. Platinum-etoposide consisted of etoposide 80-100 mg/m2 on days 1-3 of each cycle with investigator's choice of either carboplatin area under the curve 5-6 mg/mL per min or cisplatin 75-80 mg/m2 (administered on day 1 of each cycle). Patients received up to four cycles of platinum-etoposide plus durvalumab 1500 mg with or without tremelimumab 75 mg every 3 weeks followed by maintenance durvalumab 1500 mg every 4 weeks in the immunotherapy groups and up to six cycles of platinum-etoposide every 3 weeks plus prophylactic cranial irradiation (investigator's discretion) in the platinum-etoposide group. The primary endpoint was overall survival in the intention-to-treat population. We report results for the durvalumab plus platinum-etoposide group versus the platinum-etoposide group from a planned interim analysis. Safety was assessed in all patients who received at least one dose of their assigned study treatment. This study is registered at ClinicalTrials.gov, NCT03043872, and is ongoing. FINDINGS: Patients were enrolled between March 27, 2017, and May 29, 2018. 268 patients were allocated to the durvalumab plus platinum-etoposide group and 269 to the platinum-etoposide group. Durvalumab plus platinum-etoposide was associated with a significant improvement in overall survival, with a hazard ratio of 0·73 (95% CI 0·59-0·91; p=0·0047]); median overall survival was 13·0 months (95% CI 11·5-14·8) in the durvalumab plus platinum-etoposide group versus 10·3 months (9·3-11·2) in the platinum-etoposide group, with 34% (26·9-41·0) versus 25% (18·4-31·6) of patients alive at 18 months. Any-cause adverse events of grade 3 or 4 occurred in 163 (62%) of 265 treated patients in the durvalumab plus platinum-etoposide group and 166 (62%) of 266 in the platinum-etoposide group; adverse events leading to death occurred in 13 (5%) and 15 (6%) patients. INTERPRETATION: First-line durvalumab plus platinum-etoposide significantly improved overall survival in patients with ES-SCLC versus a clinically relevant control group. Safety findings were consistent with the known safety profiles of all drugs received. FUNDING: AstraZeneca.

• MeSH
• cisplatina aplikace a dávkování   škodlivé účinky   MeSH
• doba přežití bez progrese choroby MeSH
• etoposid aplikace a dávkování   škodlivé účinky   MeSH
• fytogenní protinádorové látky aplikace a dávkování   MeSH
• humanizované monoklonální protilátky aplikace a dávkování   MeSH
• karboplatina aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malobuněčný karcinom plic farmakoterapie   mortalita   MeSH
• monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• nádory plic farmakoterapie   mortalita   MeSH
• protinádorové látky imunologicky aktivní aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie MeSH
• rozvrh dávkování léků MeSH
• senioři MeSH
• Check Tag
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• cisplatina MeSH
• durvalumab MeSH Prohlížeč
• etoposid MeSH
• fytogenní protinádorové látky MeSH
• humanizované monoklonální protilátky MeSH
• karboplatina MeSH
• monoklonální protilátky MeSH
• protinádorové látky imunologicky aktivní MeSH
• tremelimumab MeSH Prohlížeč