Durvalumab ± tremelimumab + platinum-etoposide in first-line extensive-stage SCLC (ES-SCLC): Updated results from the phase III CASPIAN study.
Luís Paz-AresMikhail DvorkinYuanbin ChenNiels ReinmuthKatsuyuki HottaDmytro TrukhinGalina StatsenkoMaximilian J. HochmairMustafa ÖzgüroğluJun Ho JiОлександр ВойткоArtem PoltoratskiyFrancesco VerderameLibor HavelIgor BondarenkoJ. ArmstrongNatalie ByrneHaiyi JiangJonathan W. Goldman
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9002 Background: CASPIAN is an open-label, Phase 3 study of durvalumab (D) ± tremelimumab (T) + etoposide and either cisplatin or carboplatin (EP) for pts with 1L ES-SCLC. At the planned interim analysis (data cutoff Mar 11, 2019; 63% maturity), D + EP demonstrated a statistically significant improvement in OS compared with EP alone (HR 0.73 [95% CI 0.59–0.91]; p=0.0047). Here we present a planned updated analysis of OS for D + EP vs EP and the first results for D + T + EP vs EP. Methods: Treatment-naïve pts with ES-SCLC (WHO PS 0/1) were randomized 1:1:1 to D 1500 mg + EP q3w, D 1500 mg + T 75 mg + EP q3w, or EP q3w. In the IO arms, pts received 4 cycles of EP + D ± T, followed by maintenance D 1500 mg q4w until disease progression. Pts received one additional dose of T 75 mg post EP in the D + T + EP arm. In the EP arm, pts received up to 6 cycles of EP and optional PCI (investigator’s discretion). The two primary endpoints were OS for D + EP vs EP and for D + T + EP vs EP. Results: 268, 268 and 269 pts were randomized to D + EP, D + T + EP and EP, respectively; baseline characteristics were generally well balanced across arms. As of Jan 27, 2020, the median follow-up was 25.1 mo, 82% maturity. D + EP continued to demonstrate improvement in OS vs EP, with a HR of 0.75 (95% CI 0.62–0.91; nominal p=0.0032); median OS 12.9 vs 10.5 mo, respectively. 22.2% of pts were alive at 2 y with D + EP vs 14.4% of pts with EP. D + T + EP numerically improved OS vs EP, however this did not reach statistical significance per the prespecified statistical plan: HR 0.82 (95% CI 0.68–1.00; p=0.0451 [p≤0.0418 required for stat sig]); the median OS was 10.4 mo and 23.4% of pts were alive at 2 y. Secondary endpoints of PFS and ORR remained improved with D + EP vs EP and will be presented. Confirmed investigator-assessed ORR was similar for D + T + EP vs EP (58.4% vs 58.0%). Median PFS was similar for D + T + EP vs EP (4.9 mo vs 5.4 mo), but the 12-mo PFS rate was numerically higher (16.9% vs 5.3%); PFS HR 0.84 (95% CI 0.70–1.01). In the D + EP, D + T + EP and EP arms, respectively, incidences of all-cause AEs of Grade 3/4 were 62.3%, 70.3% and 62.8%; AEs leading to discontinuation 10.2%, 21.4% and 9.4%; and AEs leading to death 4.9%, 10.2% and 5.6%. Conclusions: The addition of durvalumab to EP continued to demonstrate improvement in OS compared with a robust control arm, further supporting this regimen as a new standard of care for 1L ES-SCLC offering the flexibility of platinum choice. No additional benefit was observed when T was combined with D + EP in this pt population. Safety findings in all arms remained consistent with the known safety profiles of all agents. Clinical trial information: NCT03043872.Keywords:
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Abstract The treatment of childhood cancer with chemotherapy drugs can result in infertility in adulthood. Newer generations of drugs are developed to replace parent drugs, with the potential benefits of less toxic side effects. For platinum alkylating-like drugs, in contrast to the parent compound cisplatin, the newer-generation drug carboplatin is reported to have reduced toxicity in some respects, despite being administered at 5–15 times higher than the cisplatin dose. Whether carboplatin is also less toxic than cisplatin to the reproductive system is unknown. Here we compare the gonadotoxic impact of cisplatin and carboplatin on female and male mouse prepubertal gonads. In vitro cultured CD1 mouse ovaries or testis fragments were exposed to either cisplatin or carboplatin for 24 h on Day 2 of culture and analysed by Day 6. A dose response for each drug was determined for the ovary (0.5, 1 & 5 μg/ml cisplatin and 1, 5 & 10 μg/ml carboplatin) and the testis (0.01, 0.05 & 0.1 μg/ml cisplatin and 0.1, 0.5 & 1 μg/ml carboplatin). For the ovary, unhealthy follicles were evident from 1 μg/ml cisplatin (73% unhealthy, P = 0.001) and 5 μg/ml carboplatin (84% unhealthy, P = 0.001), with a concomitant reduction in follicle number (P = 0.001). For the testis, the proliferating germ cell population was significantly reduced from 0.05 μg/ml cisplatin (73% reduction, P = 0.001) and 0.5 μg/ml carboplatin (75% reduction, P = 0.001), with no significant impact on the Sertoli cell population. Overall, results from this in vitro animal model study indicate that, at patient equivalent concentrations, carboplatin is no less gonadotoxic than cisplatin.
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The recurrence and prognosis of advanced cervical cancer patients is an unresolved medical need. To improve prognosis and bring new strategies to more curable stages of the disease, such as high-risk locally advanced disease patients and low metastatic or small volume disease patients. After culturing cervical cancer cells in vitro , they were treated with different concentrations of cisplatin and carboplatin drugs for 24, 48, and 72 hours respectively. Detected the inhibitory rate of different treatment groups on cervical cancer cells using CCK-8 detection, To observe live and dead cells through staining experiments. The results showed that different concentrations of cisplatin and carboplatin have significant inhibitory effects on cervical cancer cells. However, the inhibitory effect of cisplatin and carboplatin in the high concentration group on cervical cancer cells were significantly greater than that in the low concentration treatment group. The sensitivity of cervical cancer cells to cisplatin was similar with carboplatin, and the sensitivity to cisplatin was better than that of carboplatin. We believe that targeted therapy can be combined with chemotherapy drugs to enhance the anti-tumor effect of cisplatin. When the toxic side effects of cisplatin cannot be overcome, carboplatin can be considered to replace cisplatin in the treatment of cancer.
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Objective:To evaluate the effect of cisplatin and carboplatin using chemosensitivity testing,and compare their cell toxicity and provide experimental evidence for clinical application.Methods:1.The mensuration of ATP standard curve.2.An ATP-CVA test was used to determine the drug sensitivity of Hela cells、Caski cells、Siha cells.The drug were cisplatin and carboplatin and the concentration were 0.5×PPC,1×PPC and 2×PPC respectively.Results:1.In a range of 10~(-9)-10~(-5) mol/ml,there is a linear relationship between the log ATP and the log luminescence(Y=0.892X+10.257,correlation coefficient r=0.998)(P0.001).2.At the concentration of 0.5×PPC、1×PPC and 2×PPC,the restraint rate of cisplatin of Hela cells were 53.5%、69.2% and 100% respectively,the restraint rate of carboplatin of Hela cells were 56.1%、64.2% and 98% respectively;the restraint rate of cisplatin of Siha cells were 78.3%、84% and 95% repectively,the restraint rate of carboplatin of Siha cells were 69.5%、77.8% and 98% respectively;the restraint rate of cisplatin of Caski cells were 36%、45% and 52.6%,respectively,the restraint rate of carboplatin of Caski cells were 40%、41.7% and 42.3%,respectively;the differences were not significant(P0.05).Conclusion:The difference of cell toxicity between cisplatin and carboplatin was not significant,and carboplatin is better than cisplatin in the chemotherapy of cervical cancer for its little side effect.
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Objective:To provide experimental proofs for cisplatin combined with carboplatin in therapy of osteosarcoma through comparing the cytotoxity of half dose cisplatin combined with half dose carboplatin,cisplatin and arboplatin in osteosarcoma cell line(OS-732).Methods:OS-732 cells were treated by IC 50 of cisplatin,IC 50 of carboplatin,or 1/2 IC 50 cisplatin combined with 1/2 IC 50 carboplatin,and cultured 48h or 72h.Then their viability was determined by the colorimetric MTT assay.Results:When cells were cultured for 48hrs,cytotoxicities of group IC 50 cisplatin,IC 50 carboplatin and 1/2 IC 50 cisplatin+1/2 IC 50 carboplatin for OS-732 cells had no significant difference( P 0 05);when cells were cultured for 72 hrs,cytotoxicities of group IC 50 carboplatin and group 1/2 IC 50 cisplatin+1/2 IC 50 carboplatin for OS-732 cells were higher than that of group IC 50 cisplatin( P 0 05)Conclusion:Cisplatin combined with carboplatin as a “single agent” appears to be as active as cisplatin or carboplatin alone in
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The platinum drugs represent a unique and important class of antitumor agents. The initial discovery of the antitumor properties of cisplatin by Dr. Barnett Rosenberg was quickly followed by clinical trials demonstrating its efficacy in a variety of solid tumors. It was soon realized, however, that nephrotoxicity and the emergence of drug-resistant tumor cells limited the overall efficacy of cisplatin. The search for new platinum analogues that could circumvent the deleterious aspects of cisplatin therapy soon followed. Carboplatin is a cisplatin analogue that is more easily administered and is less toxic at standard doses. This is due to a different pharmacokinetic profile resulting from the substitution of a more stable leaving group. Carboplatin and cisplatin form similar DNA adducts, which may explain, in part, the similar efficacies observed with the drugs in most solid tumors. The search for platinum analogues that do not exhibit cross-resistance with cisplatin and carboplatin has led to the synthesis of the DACH platinum compounds. The DACH platinum drug, oxaliplatin, has been shown to be active in combination with 5-fluorouracil and leucovorin for the treatment of colorectal cancer, a disease in which cisplatin and carboplatin show little activity. It appears that the clinical use of cisplatin and its analogues will continue to evolve, guided by pharmacologic principles, and these drugs will remain indispensable to combination chemotherapeutic regimens for many years to come.
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Objective To observe the cytotoxicity of cisplatin combined with carboplatin on osteosarcoma cell line OS-732.Methods Using MTT assay,we obtained the mean IC50 of cisplatin and carboplatin for OS-732 cells.The OS-732 cells were incubated with following drugs for 48 or 72h: IC50 of cisplatin,IC50 of carboplatin,and 1/2 IC50 of cisplatin combined with 1/2 IC50 carboplatin.The cytotoxicity of each group was measured with MTT methods.Results The mean IC50 of cisplatin and carboplatin for osteosarcoma OS-732 cells for 48h was 7.6μg/ml and 199.0μg/ml respectively.The mean cytotoxicity index(CI) of 8.0μg/ml cisplatin, 200.0μg/ml carboplatin and 4.0μg/ml cisplatin+100.0μg/ml carboplatin for 48h were (54.7±5.3)%,(56.9±6.3)% and(57.5±5.7)% respectively(P0.05);and those for 72h were (65.7±4.5)%,(69.4±2.2)% and(68.4±3.6)% respectively,the cytotoxicity index increased significantly in groups containing carboplatin.Conclusion The combination of half dose cisplatin with carboplatin appears to be as active as cisplatin or carboplatin alone in full doses in treatment of osteosarcoma OS-732 cells in vitro.
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