Mismatch repair-deficient (dMMR) endometrial cancer (EC) is an inflamed phenotype with poor outcomes when meeting high-risk criteria and limited treatment options in the adjuvant setting. We report protocol-prespecified subgroup analysis of patients with dMMR tumors from the phase III ENGOT-en11/GOG-3053/KEYNOTE-B21 study (ClinicalTrials.gov identifier: NCT04634877) in newly diagnosed, high-risk EC after surgery with curative intent. Patients were randomly assigned to pembrolizumab 200 mg or placebo (six cycles) plus carboplatin-paclitaxel (four to six cycles) once every 3 weeks, then pembrolizumab 400 mg or placebo once every 6 weeks (six cycles), respectively. MMR status was a stratification factor. Patients received radiotherapy at investigator discretion. Investigator-assessed disease-free survival (DFS) was a primary end point. No formal hypothesis testing was performed for subgroup analysis. In the intention-to-treat population, 141 patients in the pembrolizumab arm and 140 in the placebo arm had dMMR tumors. At this interim analysis, hazard ratio for DFS favored pembrolizumab (0.31 [95% CI, 0.14 to 0.69]); median DFS was not reached in either group. Two-year DFS rates were 92.4% (95% CI, 84.4 to 96.4) and 80.2% (95% CI, 70.8 to 86.9), respectively. No new safety signals occurred. Longer-term follow-up of outcomes will be evaluated at final analysis. Preplanned subgroup analysis on the basis of the study's stratification factors suggests that pembrolizumab plus chemotherapy improves DFS and is clinically relevant for patients with dMMR tumors in the curative-intent setting.

• MeSH
• adjuvantní chemoterapie MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky * aplikace a dávkování   škodlivé účinky   terapeutické užití   MeSH
• karboplatina aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory endometria * genetika   farmakoterapie   terapie   patologie   radioterapie   MeSH
• oprava chybného párování bází DNA * MeSH
• paclitaxel aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• humanizované monoklonální protilátky * MeSH
• karboplatina MeSH
• paclitaxel MeSH
• pembrolizumab MeSH Prohlížeč

PURPOSE: Patients with high-grade serous ovarian carcinoma (HGSOC) are virtually insensitive to immune checkpoint inhibitors (ICI) employed as standalone therapeutics, at least in part reflecting microenvironmental immunosuppression. Thus, conventional chemotherapeutics and targeted anticancer agents that not only mediate cytotoxic effects but also promote the recruitment of immune effector cells to the HGSOC microenvironment stand out as promising combinatorial partners for ICIs in this oncological indication. EXPERIMENTAL DESIGN: We harnessed a variety of transcriptomic, spatial, and functional assays to characterize the differential impact of neoadjuvant paclitaxel-carboplatin on the immunological configuration of paired primary and metastatic HGSOC biopsies as compared to neoadjuvant chemotherapy (NACT)-naïve HGSOC samples from five independent patient cohorts. RESULTS: We found NACT-driven endoplasmic reticulum stress and calreticulin exposure in metastatic HGSOC lesions culminates with the establishment of a dense immune infiltrate including follicular T cells (TFH cells), a prerequisite for mature tertiary lymphoid structure (TLS) formation. In this context, TLS maturation was associated with an increased intratumoral density of ICI-sensitive TCF1+PD1+ CD8+ T cells over their ICI-insensitive TIM-3+PD1+ counterparts. Consistent with this notion, chemotherapy coupled with a PD1-targeting ICI provided a significant survival benefit over either therapeutic approach in syngeneic models of HGSOC bearing high (but not low) tumor mutational burden. CONCLUSIONS: Altogether, our findings suggest that NACT promotes TLS formation and maturation in HGSOC lesions, de facto preserving an intratumoral ICI-sensitive T-cell phenotype. These observations emphasize the role of rational design, especially relative to the administration schedule, for clinical trials testing chemotherapy plus ICIs in patients with HGSOC. See related commentary by Bravo Melgar and Laoui, p. 10.

• MeSH
• CD8-pozitivní T-lymfocyty * imunologie   účinky léků   MeSH
• ektopické lymfoidní struktury * imunologie   patologie   MeSH
• hepatocytární jaderný faktor 1-alfa * genetika   metabolismus   MeSH
• inhibitory kontrolních bodů * terapeutické užití   farmakologie   MeSH
• karboplatina aplikace a dávkování   farmakologie   terapeutické užití   MeSH
• lidé MeSH
• nádorové mikroprostředí * imunologie   účinky léků   MeSH
• nádory vaječníků * farmakoterapie   imunologie   patologie   MeSH
• neoadjuvantní terapie metody   MeSH
• paclitaxel aplikace a dávkování   terapeutické užití   farmakologie   MeSH
• protokoly protinádorové kombinované chemoterapie terapeutické užití   farmakologie   MeSH
• serózní cystadenokarcinom farmakoterapie   patologie   imunologie   MeSH
• stres endoplazmatického retikula účinky léků   imunologie   MeSH
• tumor infiltrující lymfocyty imunologie   účinky léků   metabolismus   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• Názvy látek
• hepatocytární jaderný faktor 1-alfa * MeSH
• inhibitory kontrolních bodů * MeSH
• karboplatina MeSH
• paclitaxel MeSH

OBJECTIVES: Part 1 of the RUBY trial (NCT03981796) demonstrated improved survival in patients with primary advanced or recurrent endometrial cancer (EC) treated with dostarlimab plus carboplatin-paclitaxel versus placebo plus carboplatin-paclitaxel. Here, we examine additional efficacy and safety data from patients with mismatch repair deficient/microsatellite instability-high (dMMR/MSI-H) EC in the RUBY trial. METHODS: Patients were randomized 1:1 to dostarlimab 500 mg or placebo plus carboplatin-paclitaxel every 3 weeks for 6 cycles followed by dostarlimab or placebo every 6 weeks for up to 3 years. In the dMMR/MSI-H population of RUBY Part 1, analysis of progression-free survival by investigator assessment compared with blinded independent central review, sensitivity analyses of the source-verified population compared with the randomized population, and analysis of safety in this population were completed. RESULTS: In total, 118 patients with dMMR/MSI-H were enrolled in the RUBY trial (53, dostarlimab arm; 65, placebo arm). At the first interim analysis, a 72% reduction in the risk of progression or death (P < 0.0001) was seen with dostarlimab plus carboplatin-paclitaxel by investigator assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1), which was consistent with blinded independent central review per RECIST v1.1. Likewise, sensitivity analyses of the source-verified dMMR/MSI-H population compared with the randomized dMMR/MSI-H population were consistent for progression-free survival and overall survival. Safety results seen in the dMMR/MSI-H population were similar to those previously reported for the overall population. CONCLUSIONS: All primary and secondary efficacy assessments demonstrate the consistent benefit of dostarlimab plus carboplatin-paclitaxel. The improvements seen in survival and the manageable safety profile support the favorable benefit-risk profile for dostarlimab plus carboplatin-paclitaxel in patients with dMMR/MSI-H primary advanced or recurrent EC.

• Klíčová slova
• Dostarlimab plus chemotherapy, Endometrial cancer, Immunotherapy plus chemotherapy, Primary advanced or recurrent endometrial cancer, dMMR/MSI-H endometrial cancer,
• MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky MeSH
• karboplatina aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• lokální recidiva nádoru * farmakoterapie   genetika   MeSH
• nádory endometria * farmakoterapie   genetika   patologie   MeSH
• paclitaxel aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie * škodlivé účinky   terapeutické užití   aplikace a dávkování   MeSH
• senioři MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• dostarlimab MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• karboplatina MeSH
• paclitaxel MeSH

OBJECTIVES: IMbrella A is a Phase III extension study that allowed rollover from Roche/Genentech-sponsored atezolizumab trials, including IMpower133, a Phase I/III trial of first-line atezolizumab or placebo plus carboplatin/etoposide in extensive-stage small cell lung cancer. We report outcomes from an exploratory analysis of IMpower133 with extended time-to-event data for patients who rolled over to IMbrella A. MATERIALS AND METHODS: IMpower133 patients could roll over to IMbrella A to receive atezolizumab 1200 mg intravenously every three weeks if they continued to receive atezolizumab at IMpower133 closure or were in survival follow-up after atezolizumab discontinuation. Overall survival and safety were assessed; only serious adverse events and AEs of special interest were collected in IMbrella A. RESULTS: Eighteen of 26 eligible patients rolled over to IMbrella A. At clinical cutoff (March 16, 2023), median follow-up in the atezolizumab plus carboplatin/etoposide arm (IMpower133 and IMbrella A) was 59.4 months. The three-, four-, and five-year overall survival (95 % CI) estimates were 16 % (11 %-21 %), 13 % (8 %-18 %), and 12 % (7 %-17 %), respectively. In IMbrella A, serious adverse events occurred in three patients (16.7 %), and one adverse event of special interest was reported (grade two hypothyroidism). CONCLUSION: This long-term analysis of patients from IMbrella A previously enrolled in IMpower133 provides the first report of five-year overall survival outcomes in patients with extensive-stage small cell lung cancer treated with first-line cancer immunotherapy and chemotherapy. While limited by small patient numbers and lack of long-term data for the IMpower133 control arm, exploratory overall survival analyses in patients treated with atezolizumab plus carboplatin/etoposide compared favorably with historical data with chemotherapy alone. NCT03148418.

• Klíčová slova
• Atezolizumab, Carboplatin, Clinical Trial, Drug Therapy, Etoposide, Immune Checkpoint Inhibitor, Small Cell Lung Carcinoma, Survival,
• MeSH
• dospělí MeSH
• etoposid aplikace a dávkování   terapeutické užití   MeSH
• humanizované monoklonální protilátky * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• karboplatina * aplikace a dávkování   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• malobuněčný karcinom plic * farmakoterapie   mortalita   patologie   MeSH
• míra přežití MeSH
• nádory plic * farmakoterapie   mortalita   patologie   MeSH
• následné studie MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• multicentrická studie MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• atezolizumab MeSH Prohlížeč
• etoposid MeSH
• humanizované monoklonální protilátky * MeSH
• karboplatina * MeSH

PURPOSE: Chemotherapy can potentially enhance the activity of immune checkpoint inhibitors by promoting immune priming. The phase Ib/II JAVELIN Chemotherapy Medley trial (NCT03317496) evaluated first-line avelumab + concurrent chemotherapy in patients with advanced urothelial carcinoma or non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Avelumab 800 or 1,200 mg was administered continuously every 3 weeks with standard doses of cisplatin + gemcitabine in patients with urothelial carcinoma, or carboplatin + pemetrexed in patients with nonsquamous NSCLC. Dual primary endpoints were dose-limiting toxicity (DLT; phase Ib) and confirmed objective response (phase Ib/II). RESULTS: In phase Ib, urothelial carcinoma and NSCLC cohorts received avelumab 800 mg (n = 13 and n = 6, respectively) or 1,200 mg (n = 6 each) + chemotherapy. In evaluable patients with urothelial carcinoma treated with avelumab 800 or 1,200 mg + chemotherapy, DLT occurred in 1/12 (8.3%) and 1/6 (16.7%), respectively; no DLT occurred in the NSCLC cohort. In phase II, 35 additional patients with urothelial carcinoma received avelumab 1,200 mg + chemotherapy. Across all treated patients, safety profiles were similar irrespective of avelumab dose. Objective response rates (95% confidence internal) with avelumab 800 or 1,200 mg + chemotherapy, respectively, across phase Ib/II, were 53.8% (25.1-80.8) and 39.0% (24.2-55.5) in urothelial carcinoma, and 50.0% (11.8-88.2) and 33.3% (4.3-77.7) in NSCLC. CONCLUSIONS: Preliminary efficacy and safety findings with avelumab + chemotherapy in urothelial carcinoma and NSCLC were consistent with previous studies of similar combination regimens. Conclusions about clinical activity are limited by small patient numbers. SIGNIFICANCE: This phase Ib/II trial evaluated avelumab (immune checkpoint inhibitor) administered concurrently with standard first-line chemotherapy in patients with advanced urothelial carcinoma or advanced nonsquamous NSCLC without actionable mutations. Efficacy and safety appeared consistent with previous studies of similar combinations, although patient numbers were small.

• MeSH
• cisplatina aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• deoxycytidin analogy a deriváty   aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• dospělí MeSH
• gemcitabin MeSH
• humanizované monoklonální protilátky * terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• karboplatina aplikace a dávkování   terapeutické užití   škodlivé účinky   MeSH
• karcinom z přechodných buněk farmakoterapie   patologie   MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory plic * farmakoterapie   patologie   MeSH
• nemalobuněčný karcinom plic * farmakoterapie   patologie   MeSH
• pemetrexed terapeutické užití   aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie * terapeutické užití   škodlivé účinky   aplikace a dávkování   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• urologické nádory farmakoterapie   patologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze I MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• Názvy látek
• avelumab MeSH Prohlížeč
• cisplatina MeSH
• deoxycytidin MeSH
• gemcitabin MeSH
• humanizované monoklonální protilátky * MeSH
• karboplatina MeSH
• pemetrexed MeSH

BACKGROUND: Dostarlimab is an immune-checkpoint inhibitor that targets the programmed cell death 1 receptor. The combination of chemotherapy and immunotherapy may have synergistic effects in the treatment of endometrial cancer. METHODS: We conducted a phase 3, global, double-blind, randomized, placebo-controlled trial. Eligible patients with primary advanced stage III or IV or first recurrent endometrial cancer were randomly assigned in a 1:1 ratio to receive either dostarlimab (500 mg) or placebo, plus carboplatin (area under the concentration-time curve, 5 mg per milliliter per minute) and paclitaxel (175 mg per square meter of body-surface area), every 3 weeks (six cycles), followed by dostarlimab (1000 mg) or placebo every 6 weeks for up to 3 years. The primary end points were progression-free survival as assessed by the investigator according to Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1, and overall survival. Safety was also assessed. RESULTS: Of the 494 patients who underwent randomization, 118 (23.9%) had mismatch repair-deficient (dMMR), microsatellite instability-high (MSI-H) tumors. In the dMMR-MSI-H population, estimated progression-free survival at 24 months was 61.4% (95% confidence interval [CI], 46.3 to 73.4) in the dostarlimab group and 15.7% (95% CI, 7.2 to 27.0) in the placebo group (hazard ratio for progression or death, 0.28; 95% CI, 0.16 to 0.50; P<0.001). In the overall population, progression-free survival at 24 months was 36.1% (95% CI, 29.3 to 42.9) in the dostarlimab group and 18.1% (95% CI, 13.0 to 23.9) in the placebo group (hazard ratio, 0.64; 95% CI, 0.51 to 0.80; P<0.001). Overall survival at 24 months was 71.3% (95% CI, 64.5 to 77.1) with dostarlimab and 56.0% (95% CI, 48.9 to 62.5) with placebo (hazard ratio for death, 0.64; 95% CI, 0.46 to 0.87). The most common adverse events that occurred or worsened during treatment were nausea (53.9% of the patients in the dostarlimab group and 45.9% of those in the placebo group), alopecia (53.5% and 50.0%), and fatigue (51.9% and 54.5%). Severe and serious adverse events were more frequent in the dostarlimab group than in the placebo group. CONCLUSIONS: Dostarlimab plus carboplatin-paclitaxel significantly increased progression-free survival among patients with primary advanced or recurrent endometrial cancer, with a substantial benefit in the dMMR-MSI-H population. (Funded by GSK; RUBY ClinicalTrials.gov number, NCT03981796.).

• MeSH
• dvojitá slepá metoda MeSH
• humanizované monoklonální protilátky aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory kontrolních bodů aplikace a dávkování   škodlivé účinky   MeSH
• karboplatina aplikace a dávkování   škodlivé účinky   MeSH
• lidé MeSH
• lokální recidiva nádoru * farmakoterapie   etiologie   MeSH
• mikrosatelitní nestabilita MeSH
• nádory endometria * farmakoterapie   genetika   mortalita   patologie   MeSH
• oprava chybného párování bází DNA MeSH
• paclitaxel aplikace a dávkování   škodlivé účinky   MeSH
• protokoly protinádorové kombinované chemoterapie * škodlivé účinky   terapeutické užití   MeSH
• Check Tag
• lidé MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze III MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• dostarlimab MeSH Prohlížeč
• humanizované monoklonální protilátky MeSH
• inhibitory kontrolních bodů MeSH
• karboplatina MeSH
• paclitaxel MeSH

OBJECTIVE: DCVAC/OvCa is an active cellular immunotherapy designed to stimulate an immune response against ovarian cancer. We explored the safety and efficacy of DCVAC/OvCa plus carboplatin and gemcitabine in platinum-sensitive ovarian cancer. METHODS: In this open-label, parallel-group, phase 2 trial (ClinicalTrials.gov number NCT02107950), patients with platinum-sensitive ovarian cancer relapsing after first-line chemotherapy were randomized to DCVAC/OvCa and chemotherapy or chemotherapy alone. DCVAC/OvCa was administered every 3-6 weeks (10 doses). Endpoints included safety, progression-free survival (PFS; primary efficacy endpoint) and overall survival (OS; secondary efficacy endpoint). RESULTS: Between November 2013 and May 2015, 71 patients were randomized to chemotherapy in combination with DCVAC/OvCa or to chemotherapy alone. Treatment-emergent adverse events related to DCVAC/OvCa, leukapheresis and chemotherapy occurred in six (16.2%), two (5.4%), and 35 (94.6%) patients in the DCVAC/OvCa group. Chemotherapy-related events occurred in all patients in the chemotherapy group. Seven patients in the DCVAC/OvCa group were excluded from primary efficacy analyses due to failure to receive ≥1 dose of DCVAC/OvCa. PFS was not improved (hazard ratio [HR] 0.73, 95% confidence interval [CI] 0.42-1.28, P = 0.274, data maturity 78.1%). Median OS was significantly prolonged (by 13.4 months) in the DCVAC/OvCa group (HR 0.38, 95% CI 0.20-0.74, P = 0.003; data maturity 56.3%). A signal for enhanced surrogate antigen-specific T-cell activity was seen with DCVAC/OvCa. CONCLUSIONS: DCVAC/OvCa combined with chemotherapy had a favorable safety profile in patients with platinum-sensitive ovarian cancer. DCVAC/OvCa did not improve PFS, but the exploratory analyses revealed OS prolongation and enhanced surrogate antigen-specific T-cell activity.

• Klíčová slova
• Dendritic-cell based immunotherapy, Immunogenic cell death, Ovarian cancer,
• MeSH
• dendritické buňky imunologie   transplantace   MeSH
• deoxycytidin aplikace a dávkování   analogy a deriváty   MeSH
• dospělí MeSH
• epiteliální ovariální karcinom terapie   MeSH
• gemcitabin MeSH
• imunoterapie adoptivní škodlivé účinky   metody   MeSH
• karboplatina aplikace a dávkování   MeSH
• kombinovaná terapie MeSH
• lidé středního věku MeSH
• lidé MeSH
• nádory vaječníků farmakoterapie   imunologie   patologie   terapie   MeSH
• protokoly protinádorové kombinované chemoterapie škodlivé účinky   terapeutické užití   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• klinické zkoušky, fáze II MeSH
• multicentrická studie MeSH
• práce podpořená grantem MeSH
• randomizované kontrolované studie MeSH
• Názvy látek
• deoxycytidin MeSH
• gemcitabin MeSH
• karboplatina MeSH

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

AGO-OVAR 12 investigated the effect of adding the oral triple angiokinase inhibitor nintedanib to standard front-line chemotherapy for advanced ovarian cancer. At the primary analysis, nintedanib demonstrated significantly improved progression-free survival (PFS; primary endpoint) compared with placebo. We report final results, including overall survival (OS). Patients with primary debulked International Federation of Gynaecology and Obstetrics (FIGO) stage IIB-IV newly diagnosed ovarian cancer were randomised 2:1 to receive carboplatin (area under the curve 5 or 6) plus paclitaxel (175 mg/m2 ) on day 1 every 3 weeks for six cycles combined with either nintedanib 200 mg or placebo twice daily on days 2-21 every 3 weeks for up to 120 weeks. Between December 2009 and July 2011, 1,366 patients were randomised (911 to nintedanib, 455 to placebo). Disease was considered as high risk (FIGO stage III with >1 cm residuum, or any stage IV) in 39%. At the final analysis, 605 patients (44%) had died. There was no difference in OS (hazard ratio 0.99, 95% confidence interval [CI] 0.83-1.17, p = 0.86; median 62.0 months with nintedanib vs. 62.8 months with placebo). Subgroup analyses according to stratification factors, clinical characteristics and risk status showed no OS difference between treatments. The previously reported PFS improvement seen with nintedanib did not translate into an OS benefit in the nonhigh-risk subgroup. Updated PFS results were consistent with the primary analysis (hazard ratio 0.86, 95% CI 0.75-0.98; p = 0.029) favouring nintedanib. The safety profile was consistent with previous reports.

• Klíčová slova
• antiangiogenic, nintedanib, ovarian cancer, overall survival, tyrosine kinase inhibitor,
• MeSH
• adjuvantní chemoterapie škodlivé účinky   metody   MeSH
• cytoredukční chirurgie MeSH
• doba přežití bez progrese choroby MeSH
• dospělí MeSH
• indoly aplikace a dávkování   škodlivé účinky   MeSH
• inhibitory proteinkinas aplikace a dávkování   škodlivé účinky   MeSH
• karboplatina aplikace a dávkování   škodlivé účinky   MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• nádory vaječníků mortalita   patologie   terapie   MeSH
• následné studie MeSH
• ovarium patologie   chirurgie   MeSH
• paclitaxel aplikace a dávkování   škodlivé účinky   MeSH
• placebo MeSH
• protokoly protinádorové kombinované chemoterapie aplikace a dávkování   škodlivé účinky   MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• staging nádorů MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mladý dospělý MeSH
• senioři nad 80 let 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
• indoly MeSH
• inhibitory proteinkinas MeSH
• karboplatina MeSH
• nintedanib MeSH Prohlížeč
• paclitaxel MeSH
• placebo MeSH

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