培美曲塞联合铂类一线治疗晚期非鳞非小细胞肺癌的临床观察

背景与目的：晚期肺癌一线化疗有效率仅30%～40%,本研究旨在探讨培美曲塞联合铂类药物(卡铂或顺铂)治疗晚期非鳞非小细胞肺癌(non-small cell lung cancer,NSCLC)的疗效及不良反应。方法：121例非鳞NSCLC患者,给予培美曲塞联合铂类化疗：培美曲塞500 mg/m2第1天,静脉滴注,卡铂300 mg/m2,第1天,静脉滴注,每3周重复;或培美曲塞500 mg/m2,第1天,静脉滴注,顺铂70 mg/m2,第1天,静脉滴注,每3周重复。上述方案连用2~6个周期,至少2个周期评价疗效。主要观察终点是疾病控制率(diseasecontrol rate,DCR),其次是中位无进展生存时间(progression-free survival,PFS)、1年生存率和安全性。结果：全组可评价疗效121例,完全缓解(complete response,CR)1例,部分缓解(partial response,PR)44例,病情稳定(stable disease,SD)50例,疾病进展(progressive disease,PD)26例,客观有效率(objective response rate,ORR)为37.2%(45/121),DCR为78.5%(95/121),PFS为5.2个月(95%CI：4.4~6.0个月),1年生存率为59.0%。其中培美曲塞联合卡铂组ORR为38.3%(23/60),DCR为78.3%(47/60),PFS为5.1个月(95%CI：3.8~6.4个月),1年生存率55.2%;培美曲塞联合顺铂组ORR为36.1%(22/61),DCR为78.7%(48/61),PFS为6.2个月(95%CI：4.3~8.1个月),1年生存率为62.5%。两组之间的ORR、DCR、PFS和1年生存率差异无统计学意义(P＞0.05)。主要不良反应为中性粒细胞和白细胞下降、乏力及胃肠道反应。结论：培美曲塞联合铂类药物一线治疗晚期非鳞NSCLC疗效确切,不良反应发生率低,耐受性较好。     

A Randomized Phase II Study of Pemetrexed in Combination With Cisplatin or Carboplatin as First-Line Therapy for Patients With Locally Advanced or Metastatic Non–Small-Cell Lung Cancer

BackgroundPemetrexed plus cisplatin was approved for first-line treatment of non–small-cell lung cancer (NSCLC) in patients with nonsquamous histology after initiation of this study. This phase II study evaluated pemetrexed plus cisplatin and pemetrexed plus carboplatin as first-line treatments for stage IIIB/IV NSCLC.Patients and MethodsThe patients were randomized (1:1) to 2 parallel arms: pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²) or pemetrexed (500 mg/m²) plus carboplatin (area under the curve 6) day 1 every 3 weeks (maximum, 6 cycles). Progression-free survival (PFS) was the primary objective; secondary objectives included overall survival (OS), 1-year survival, and safety.ResultsSixty-five patients were randomized to each treatment arm. The patients treated with pemetrexed plus cisplatin had a median age of 64 years and were predominantly men (42 [64.6%]) with nonsquamous histology (53 [81.5%]), stage IV (61 [92.4%]) disease, and a performance status of 0 (40 [61.5%]). Median PFS was 6.0 months, 6-month PFS rate was 50.5%, median OS was 11.7 months, and 1-year survival rate was 47.5%. Drug-related grade 3/4 toxicities included neutropenia (11 [16.9%]), anemia (5 [7.7%]), thrombocytopenia (2 [3.1%]), and nausea (3 [4.6%]). Patients treated with pemetrexed plus carboplatin had a median age of 63 years, were predominantly men (46 [70.8%]) with nonsquamous histology (52 [80.0%]), stage IV (58 [86.6%]) disease, and a performance status of 0 (45 [69.2%]). The median PFS was 4.7 months, the 6-month PFS rate was 34.9%, median OS was 8.9 months, and 1-year survival rate was 39.2%. Drug-related grade 3/4 toxicities included neutropenia (17 [26.2%]), thrombocytopenia (11 [16.9%]), anemia (7 [10.8%]), and nausea (5 [7.7%]).ConclusionsBoth the pemetrexed plus cisplatin and pemetrexed plus carboplatin arms met their primary endpoints and demonstrated efficacy and tolerability as first-line therapy in patients with advanced NSCLC. http://ClinicalTrials.gov: NCT00402051.     

Pemetrexed in the treatment of advanced non-small-cell lung cancer: a review of the clinical data

Pemetrexed is a novel multitargeting antimetabolite that has first-line and second-line activity against non-small cell lung cancer (NSCLC). Phase II studies have shown significant efficacy and a favorable toxicity profile of the combination of pemetrexed plus platinum as first-line therapy for NSCLC. Second-line activity against NSCLC was demonstrated in a phase III trial comparing single-agent pemetrexed with docetaxel; in that trial, survival was comparable between these agents but side effects were significantly less for patients who received pemetrexed. Pemetrexed is also an active agent against mesothelioma. A phase III trial comparing pemetrexed plus cisplatin with cisplatin alone showed for the first time a regimen that improves survival in this disease and led to FDA approval of pemetrexed in combination with cisplatin for mesothelioma. As a radiosensitizer, pemetrexed has been well-tolerated when given concurrent with chest radiation, and a phase I study is under way assessing its tolerability in combination with carboplatin in this setting. Pemetrexed is clearly a useful agent in the treatment of thoracic malignancies, and is worthy of further study in combination with other drugs having novel mechanisms of action.     

Chemotherapy management of malignant pleural mesothelioma: a phase II study comparing two popular chemotherapy regimens

Purpose

The aim of this prospective, phase II clinical study is to evaluate the activity of gemcitabine and cisplatin in comparison to pemetrexed and carboplatin in patients with malignant pleural mesothelioma.

Patients and methods

The patients were recruited from May 2008 to May 2011. One group included 21 cases who received cisplatin and gemcitabine. The other group included 19 cases who received pemetrexed and carboplatin.

Results

Response is superior in the pemetrexed group (p = 0.041). The median follow-up was 18 months (range 6–30 months). Cumulative survival at 1.5 years was 57.8 % for the pemetrexed carboplatin group. For the gemcitabine cisplatin group, the cumulative survival proportion at 1.5 years was 41 % (p = 0.0599).

Conclusions

Pemetrexed plus carboplatin are a step forward in the treatment of mesothelioma, the prognosis for these patients remains poor. Cheaper combinations as gemcitabine and cisplatin may be considered sufficient to treat cases with advanced mesothelioma.     

Overview on ongoing or planned clinical trials in Europe

Malignant pleural mesothelioma (MPM) is a locally invasive malignancy, but only a minority of patients can benefit by surgical resection. Among chemotherapeutic agents only vinorelbine, edatrexate, gemcitabine and raltitrexed have demonstrated response rates >20%. The largest randomised trial in MPM showed an improved median survival with cisplatin and pemetrexed versus cisplatin alone from 9.3 to 12.1 months. For the present overview about 70 requests of information were sent to the major European centres of thoracic oncology. The most widespread study treatment in Europe is an 'Extended Access Program (EAP)' evaluating pemetrexed alone or combined with cisplatin or carboplatin with about 1500 enrolled patients. Two other international randomized studies compare pemetrexed plus best supportive care (BSC) versus BSC alone, and the role of Ranpirnase (Onconase) in MPM. Important national trials are ongoing: in the UK the addressed questions were the role of radical surgery (MARS Trial), the role of chemotherapy (MS-01 trial) and the role of VATS on active treatment of pleural effusion. In Switzerland the SAKK group phase III study explores in a comparative way the value of hemithoracic radiotherapy after primary treatment with cisplatin/pemetrexed followed by surgery. In Italy, 2 phase II trials of neoadjuvant chemotherapy (pemetrexed plus cisplatin in Rome, pemetrexed plus carboplatin in Padua) followed by surgery and radiotherapy are active. With the important exception of UK, the most evident element is the overwhelming presence of pemetrexed in the ongoing and future clinical trials. Pemetrexed has influenced not only the clinical practice, but also the patient enrolment in clinical trials.     

Superiority of high-dose platinum (cisplatin and carboplatin) compared to carboplatin alone in combination chemotherapy for small-cell lung carcinoma: A prospective randomised trial of 280 consecutive patients

Purpose:A prospective randomized trial in small-cell lung cancer (SCLC) was performed to determine if intensification of the platinum dose by giving cisplatin and carboplatin in combination to patients with SCLC yields higher response rates and survival, than carboplatin alone in a combination chemotherapy regimen. Patients and methods:Between September 1992 and October 1997, 280 patients were included in a two armed prospective randomized trial, stratified by stage of disease, LDH and performance status. The treatment was in arm A: three courses induction chemotherapy with carboplatin (AUC = 4, day 1), cisplatin (35 mg/m², days 2 and 3), teniposide (50 mg/m², day 1–5), vincristine (1.3 mg/m², day 1) every four weeks, followed by cyclophosphamide (3 g/m², day 84), 4-epirubicin (4-epidoxorubicin) (150 mg/m², day 112), and finally one course cisplatin, carboplatin, teniposide and vincristine, (days 140–144). Arm B also comprised a total of six courses, identical to those in arm A except for omission of cisplatin. Results:There were no significant differences in the overall treatment outcome for A vs. B, in terms of response rates (72% in both arms), complete response rates (40% and 34%, respectively), or median survival (314 days and 294 days, respectively). However, for patients with limited disease both the CR rate (54% vs. 37%, P < 0.05), overall survival (log-rank test,P < 0.05), and the two-year survival rate (11% vs. 6%,P < 0.05) were higher in the high-dose platinum arm compared to the carboplatin alone arm. Conclusions:The intensification of platinum dose (cisplatin plus carboplatin) in combination chemotherapy significantly increased the complete response rate, overall survival and number of two-year survivors among SCLC patients with limited disease compared to combination therapy with carboplatin alone, suggesting that a more aggressive treatment to this category of patients is worthwhile, while no difference in treatment outcome was observed for patients with extensive disease.     

Pemetrexed in combination with cisplatin versus cisplatin monotherapy in patients with recurrent or metastatic head and neck cancer: Final results of a randomized, double-blind, placebo-controlled, phase 3 study

BACKGROUND:

Recurrent or metastatic squamous cell carcinoma of the head and neck (SCCHN) is associated with poor survival. Platinum‐based chemotherapy is often a first‐line treatment. Pemetrexed has shown single‐agent activity in SCCHN and in combination with cisplatin for other tumors. This trial examined the efficacy of pemetrexed‐cisplatin for SCCHN.

METHODS:

In a double‐blind phase 3 trial, patients with recurrent or metastatic SCCHN and no prior systemic therapy for metastatic disease were randomized to pemetrexed (500 mg/m²) plus cisplatin (75 mg/m²; n = 398) or placebo plus cisplatin (75 mg/m²; n = 397) to assess overall survival (OS) and secondary endpoints.

RESULTS:

Median OS was 7.3 months in the pemetrexed‐cisplatin arm and 6.3 months in the placebo‐cisplatin arm (hazard ratio [HR], 0.87; 95% confidence interval [CI], 0.75‐1.02; P = .082). Median progression‐free survival (PFS, months) was similar in both treatment arms (pemetrexed‐cisplatin, 3.6; placebo‐cisplatin, 2.8; HR, 0.88; 95% CI, 0.76‐1.03; P = .166). Among patients with performance status 0 or 1, pemetrexed‐cisplatin (n = 347) led to longer OS and PFS than placebo‐cisplatin (n = 343; 8.4 vs 6.7 months; HR, 0.83; P = .026; 4.0 vs 3.0 months; HR, 0.84; P = .044, respectively). Among patients with oropharyngeal cancers, pemetrexed‐cisplatin (n = 86) resulted in longer OS and PFS than placebo‐cisplatin (n = 106; 9.9 vs 6.1 months; HR, 0.59; P = .002; 4.0 vs 3.4 months; HR, 0.73; P = .047, respectively). Pemetrexed‐cisplatin toxicity was consistent with studies in other tumors.

CONCLUSIONS:

Pemetrexed‐cisplatin compared with placebo‐cisplatin did not significantly improve survival for the intent‐to‐treat population. However, in a prespecified subgroup analysis, pemetrexed‐cisplatin showed OS and PFS advantage for patients with performance status 0 or 1 or oropharyngeal cancers. Cancer 2012. © 2012 American Cancer Society.     

Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma.

PURPOSE: Patients with malignant pleural mesothelioma, a rapidly progressing malignancy with a median survival time of 6 to 9 months, have previously responded poorly to chemotherapy. We conducted a phase III trial to determine whether treatment with pemetrexed and cisplatin results in survival time superior to that achieved with cisplatin alone. PATIENTS AND METHODS: Chemotherapy-naive patients who were not eligible for curative surgery were randomly assigned to receive pemetrexed 500 mg/m2 and cisplatin 75 mg/m2 on day 1, or cisplatin 75 mg/m2 on day 1. Both regimens were given intravenously every 21 days. RESULTS: A total of 456 patients were assigned: 226 received pemetrexed and cisplatin, 222 received cisplatin alone, and eight never received therapy. Median survival time in the pemetrexed/cisplatin arm was 12.1 months versus 9.3 months in the control arm (P =.020, two-sided log-rank test). The hazard ratio for death of patients in the pemetrexed/cisplatin arm versus those in the control arm was 0.77. Median time to progression was significantly longer in the pemetrexed/cisplatin arm: 5.7 months versus 3.9 months (P =.001). Response rates were 41.3% in the pemetrexed/cisplatin arm versus 16.7% in the control arm (P <.0001). After 117 patients had enrolled, folic acid and vitamin B12 were added to reduce toxicity, resulting in a significant reduction in toxicities in the pemetrexed/cisplatin arm. CONCLUSION: Treatment with pemetrexed plus cisplatin and vitamin supplementation resulted in superior survival time, time to progression, and response rates compared with treatment with cisplatin alone in patients with malignant pleural mesothelioma. Addition of folic acid and vitamin B12 significantly reduced toxicity without adversely affecting survival time.     

培美曲塞联合顺铂在晚期男性肺腺癌一线治疗中的应用

目的：观察培美曲塞联合顺铂（PP组）与吉西他滨联合顺铂（GP组）作为一线化疗药物治疗晚期男性肺腺癌的疗效及毒副反应.方法：将74例经病理证实的晚期男性肺腺癌患者（Ⅲb和Ⅳ期）分为两组：GP组40例,PP组34例.PP组：培美曲塞500mg/m2,静脉滴注,第1天,持续3-4h;顺铂（DDP） 75 mg/m2,静脉点滴,第1天,每21天为1个周期.GP组：吉西他滨1250mg/m2,静脉点滴,第1、8天;顺铂用法同上,每3周为1个周期.连续4-6个周期.每2周期评价疗效及毒副反应.结果：PP组总有效率[完全缓解（CR）＋部分缓解（PR）]为44.1％,1年生存率为38.2％;GP组总有效率为42.5％,1年生存率为37.5％,两组间总有效率和1年生存率比较均无统计学意义（P＞0.05）.最常见的毒副反应是骨髓抑制和胃肠道反应,其中骨髓抑制两组间比较差异有统计学意义（P＜0.05）.结论：培美曲塞联合顺铂方案可作为一线治疗晚期男性肺腺癌的选择.     

Dose escalation study of carboplatin–pemetrexed followed by maintenance pemetrexed for elderly patients with advanced nonsquamous nonsmall-cell lung cancer

BackgroundThis study was designed to determine the recommended dose of carboplatin–pemetrexed in elderly (≥75 years old), chemotherapy-naive patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC).Patients and methodsPatients received escalated doses of carboplatin and pemetrexed every 3 weeks for four cycles. Patients with an objective response and stable disease continued pemetrexed therapy until disease progression or unacceptable toxicity was observed.ResultsThe combination of carboplatin at an area under the concentration–time curve (AUC) of 5, and 500 mg/m² pemetrexed, was determined to be the recommended dose for elderly patients with advanced nonsquamous NSCLC. Of 17 patients, 10 received a median of five cycles of pemetrexed maintenance therapy without unexpected or cumulative toxic effects. The study had an overall response rate of 47.1%. The median progression-free survival time was 142 days (95% confidence interval [CI] 68–216 days) and the median overall survival time was 461 days (95% CI 168–754 days).ConclusionsThis combination was a tolerable and effective regimen, and recommended dose (RD) was carboplatin [area under the curve (AUC) of 5]/pemetrexed (500 mg/m²) every 3 weeks, in chemotherapy-naïve, elderly (≥75 years old) patients with advanced nonsquamous NSCLC.     

Platinum-based doublet chemotherapy in pre-treated malignant pleural mesothelioma (MPM) patients: a mono-institutional experience

Background

The major clinical problems of MPM management are the short duration of response and the early relapse. Currently, after the first-line standard pemetrexed/platinum combination there is not a defined regimen for the second line treatment of MPM, and the clinical benefits in fit patients are uncertain. We analyzed the feasibility of gemcitabine/platinum chemotherapy in pretreated MPM patients.

Methods

Eligible patients should have relapsed after first-line chemotherapy with pemetrexed plus cisplatin (24%) or carboplatin (76%); 53% of the patients had previously received trimodality treatment, 18% neoadjuvant chemotherapy followed by pleurectomy/decortication, 29% were inoperable. Patients had to have PS = 0-2, adequate organ function, measurable disease.Chemotherapy was gemcitabine 1000 mg/m² days 1, 8 associated to the alternative platinum compound respect to 1st line, i.e. cisplatin 75 mg/m² or carboplatin AUC 5 day 1 every 3 weeks, for 3-6 cycles. Baseline staging and reassessment after cycles 3 and 6 were performed with CT-scan.

Results

Since 2006 17 relapsed MPM patients were referred to our centre. Patients were 12 males and 5 females; median age: 61 years (range 47-74); histology: 12 epithelial, 4 sarcomatoid and 1 biphasic. PS 1-2 (15:2).The combination of gemcitabine with carboplatin/cisplatin was administered as second line treatment in 13 (76%) patients, as third line in 4 (24%) patients. Two patients were lost to follow-up without re-evaluation, therefore radiologic and clinical response was assessable in 15 (88%) patients. Among evaluable patients 10 (67%) showed stable disease and 5 (33%) progressive disease. Symptoms improved in 8 (53%) cases. In the intent-to-treat population median survival was 28 weeks (range 13-168) and median time-to-treatment failure 15 weeks (range 3-75).Toxicity profile showed 2 (13%) grade 4 and 6 (40%) grade 3 thrombocytopenia, 4 (27%) grade 3 leucopenia, 3 (20%) grade 3 anaemia and 6 (40%) of grade 3 neutropenia. Grade 3 non haematological toxicities were nausea (14%) and asthenia (21%).

Conclusion

Gemcitabine-platinum regimens are able to control symptoms and disease progression with a modest toxicity profile. The present results from a small series of patients should be confirmed by a prospective trial in a larger cohort of patients.     

A phase II study of pemetrexed and carboplatin in patients with locally advanced or metastatic breast cancer

BACKGROUND: Pemetrexed and carboplatin have demonstrated activity in breast cancer. Their potential synergism in experimental models and the proven efficacy of pemetrexed/platinum in other indications make pemetrexed/carboplatin an attractive combination in breast cancer. Thus, this two-stage, sequential, open-label, multicenter, phase II study assessed the efficacy and safety of pemetrexed plus carboplatin as first-line therapy in patients with locally advanced breast cancer (LABC) or metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients >/= 18 years with a histologic/cytologic diagnosis and no prior chemotherapy for LABC or MBC received pemetrexed 600 mg/m(2) and carboplatin AUC 5.0 on day 1 every 21 days with folic acid and vitamin B(12) supplementation. RESULTS: From June 2003 to April 2005, 50 patients with stage IIIB (30.0%) and stage IV (70.0%) disease were enrolled at 3 study centers. Twenty-eight percent of patients previously received adjuvant chemotherapy, 46.0% had visceral metastases, and 36.0% had >/=3 organs involved. Partial responses (RECIST criteria) were achieved in 27 (54.0%) patients (ORR = 54.0%; 95% CI, 39.3-68.2%). The median response duration was 11.1 months (95% CI, 6.5-14.0 months) and the median time to disease progression was 10.3 months (95% CI, 8.3-14.6 months). CTC hematologic toxicities were grade 3/4 neutropenia (58.0%/28.0%) and grade 3 thrombocytopenia (10.0%) and anemia (18.0%). Two (4.0%) patients had febrile neutropenia, 1 of whom died. No grade 4 non-hematologic toxicities occurred. Grade 3 non-hematologic toxicities were ALT (4.0%) and AST elevation, and edema, fatigue, pruritus, rash/desquamation, and renal toxicity (2.0% each). CONCLUSIONS: Results of this study suggest that the combination of pemetrexed and carboplatin has promising efficacy and an acceptable safety profile. Further assessment of this combination in a randomized trial of various breast cancer patient populations is warranted.     

Comparison of Patient Outcomes According to Histology Among Pemetrexed-Treated Patients With Stage IIIB/IV Non–Small-Cell Lung Cancer in Two Phase II Trials

IntroductionRecent phase III studies in advanced non–small-cell lung cancer (NSCLC) have demonstrated differential efficacy for pemetrexed according to NSCLC histology. The results of 2 phase II studies of pemetrexed and a platinum agent (carboplatin or oxaliplatin) were pooled to determine whether outcomes in the studies differed by tumor histology.Patients and MethodsChemotherapy-naive patients with stage IIIB/IV NSCLC received pemetrexed 500 mg/m² plus carboplatin area under the curve of 6 (n = 89) or pemetrexed 500 mg/m² plus oxaliplatin 120 mg/m² (n = 41); both regimens were administered every 21 days. The primary endpoint of both trials was response rate. Treatment arms were pooled, and Cox models with main effects for squamous histology were used to assess overall survival and progression-free survival. Cofactor adjustments incorporated terms for performance status, disease stage, and sex.ResultsMore than three quarters of enrolled patients had a nonsquamous histology. Mean age was 59.9 years for patients with nonsquamous histology and 63.7 years for patients with squamous histology. Response rates were 30% for patients with nonsquamous histology and 17.2% for patients with squamous histology. Overall survival was 10.5 months for patients with nonsquamous histology and 9.8 months for patients with squamous histology (hazard ratio [HR], 0.95; 95% CI, 0.52-1.74). Progression-free survival was 5.6 months for patients with nonsquamous histology and 4.7 months for patients with squamous histology (HR, 0.72; 95% CI, 0.43-1.19).ConclusionIn patients treated with pemetrexed/platinum doublets, nonsquamous histology was associated with better outcomes. The benefit of pemetrexed treatment among patients with nonsquamous histology is consistent with the results reported from previous studies.     

Cisplatin and carboplatin combination as second-line chemotherapy in dacarbazine-resistant melanoma patients

High-dose cisplatin regimens have been shown to be highly active in advanced melanoma patients but are associated with unacceptable side effects. In order to increase the platinum dose but avoid severe side effects, we treated 15 dacarbazine (DTIC)-resistant metastatic melanoma patients with a combination regimen of cisplatin (100 mg/m2) and carboplatin (200 mg/m2), two platinum analogues with a similar mode of action but a different toxicity pattern. After a mean follow-up period of 10.7 months (range 4-18 months), two patients (13.3%) achieved complete remission and two patients (13.3%) showed partial remission, giving an overall response rate of 26.4% (95% confidence interval [CI] 4.2-49%). Furthermore, three patients (20%; 95% CI 0-40.2%) experienced stable disease. The median duration of response was 7.1 months (95% CI 4.2-10.0 months), and the median overall survival was 12.5 months (95% CI 5.8-19.2 months), with eight patients still alive. The main side effects were haematological (leukopenia/thrombocytopenia World Health Organization [WHO] grade I-IV; anaemia WHO grade I-III), gastrointestinal (WHO grade I-III), neurological (WHO grade I-II) and renal (WHO grade I) toxicity. Nevertheless, except in one patient, side effects did not result in discontinuation of therapy. Despite the small number of patients treated in this preliminary study, we believe that combining cisplatin and carboplatin represents a novel, active and well-tolerated therapeutic option as second-line chemotherapy in DTIC-resistant advanced melanoma patients.     

Tislelizumab Plus Chemotherapy as First-Line Treatment for Locally Advanced or Metastatic Nonsquamous NSCLC (RATIONALE 304): A Randomized Phase 3 Trial

IntroductionTislelizumab, an anti–programmed cell death protein-1 antibody, was specifically engineered to minimize FcɣR macrophage binding to abrogate antibody-dependent phagocytosis. Compared with chemotherapy alone, tislelizumab plus chemotherapy may improve clinical outcomes in patients with advanced nonsquamous NSCLC (nsq-NSCLC).MethodsIn this open-label phase 3 trial (RATIONALE 304; NCT03663205), patients with histologically confirmed stage IIIB or IV nsq-NSCLC were randomized (2:1) to receive either arm A: tislelizumab plus platinum (carboplatin or cisplatin) and pemetrexed every 3 weeks (Q3Ws) or arm B: platinum and pemetrexed alone Q3W during induction treatment, followed by intravenous maintenance pemetrexed Q3W. The primary end point was progression-free survival (PFS) assessed by an independent review committee; clinical response and safety and tolerability were secondary end points.ResultsOverall, 332 patients (n = 222 [A]; n = 110 [B]) received treatment. With a median study follow-up of 9.8 months, PFS was significantly longer with tislelizumab plus chemotherapy compared with chemotherapy alone (median PFS: 9.7 versus 7.6 mo; hazard ratio = 0.645 [95% confidence interval: 0.462–0.902], p = 0.0044). In addition, response rates were higher and response duration was longer with combination therapy versus chemotherapy alone. Hematologic adverse events (AEs) were common in both treatment arms; the most reported AEs were grades 1 to 2 in severity. The most common grade greater than or equal to 3 AEs were associated with chemotherapy and included neutropenia (44.6% [A]; 35.5% [B]) and leukopenia (21.6% [A]; 14.5% [B]).ConclusionsAddition of tislelizumab to chemotherapy resulted in significantly prolonged PFS, higher response rates, and longer response duration compared with chemotherapy alone, identifying a new potential option for first-line treatment of advanced nsq-NSCLC irrespective of disease stage.     

Pemetrexed

? Pemetrexed inhibits several folate-dependent enzymes, thereby inhibiting both thymidine synthesis and purine nucleotide synthesis. ? The median survival time of patients with NSCLC treated with pemetrexed 500 mg/m² monotherapy every 21 days versus docetaxel 75 mg/m² every 21 days in a second-line setting was 8.3 and 7.9 months (hazard ratio = 0.99, 95% CI 0.82-1.20, with a preset 95% CI upper limit of <1.11) in a phase III randomized, nonblind, multicenter trial (n = 571). In a phase III randomized, single-blind, multicenter trial (n = 448) in chemotherapy-naive patients with malignant pleural mesothelioma (MPM), pemetrexed 500 mg/m² plus cisplatin 75 mg/m² every 21 days was better in terms of median survival time (12.1 vs 9.3 months; hazard ratio 0.77, p < 0.05) and tumor response rates (41.3% vs 16.7%, p < 0.001) than cisplatin 75 mg/m² every 21 days. ? During the MPM trial, a protocol change required all patients to receive supplementation with oral folic acid daily and intravenous cyanocobalamin once every 9 weeks (i.e. supplementation) because of pemetrexed toxicity. ? Pemetrexed was generally well tolerated as monotherapy in patients with advanced NSCLC and as combination therapy in patients with MPM if supplemented. In patients with NSCLC, neutropenia, alopecia, and fatigue were the most common adverse events, whereas in patients with MPM they were neutropenia, leukopenia, nausea, and vomiting. Severe toxicities in pemetrexed recipients in the NSCLC trial were infrequent.

培美曲塞治疗EGFR-TKI获得性耐药的晚期非小细胞肺癌疗效观察

目的观察培美曲塞治疗EGFR-TKI获得性耐药的晚期非小细胞肺癌（非鳞癌）的疗效。方法14例患者入组,2例既往未接受化疗患者采用培美曲塞联合顺铂方案,培美曲塞 500 mg/m2,静脉滴注,d1;DDP 25 mg/m2,静脉滴注d1~d3。12例既往曾接受含铂两药联合方案化疗患者（不含培美曲塞）,采用培美曲塞单药化疗500 mg/m2,d1;21天为一周期。所有患者均接受2周期以上治疗。结果14例患者均接受2周期以上治疗,可评价疗效。治疗有效率35.7%（5/14）,疾病控制率71.4%（10/14）,中位疾病进展时间（PFS）为6.3月,中位生存期为12.5月。结论培美曲塞治疗EGFR-TKI治疗失败后晚期非小细胞肺癌取得一定疗效,不良反应可以耐受,值得临床进一步研究。     

紫杉醇脂质体联合卡铂治疗培美曲塞联合顺铂化疗失败的晚期肺腺癌的临床观察

目的:探讨紫杉醇脂质体联合卡铂治疗培美曲塞联合顺铂化疗失败的晚期肺腺癌的临床疗效及安全性.方法:收集2012年1月至2015年4月22例对培美曲塞联合顺铂方案化疗失败的晚期肺腺癌患者,给予紫杉醇脂质体联合卡铂治疗,具体用药:紫杉醇脂质体175 mg/m2,静脉滴注,第1天;卡铂AUC 5,静脉滴注,第1天,21天为1个周期.至少化疗2个周期后评价疗效及不良反应.结果:全组22例患者均可评价疗效和不良反应.获完全缓解(complete response,CR)0例,部分缓解(partial response,PR)10例,稳定(stable disease,SD)8例,进展(progression disease,PD)4例,有效率(response rate,RR)为45.5%,疾病控制率(disease control rate,DCR)81.8%,中位无进展生存时间(progression free survival,PFS)5.6个月,中位总生存时间(overall survival,OS)9.5个月,1年生存率36.4%.主要不良反应为骨髓抑制,经对症处理后均缓解.结论:紫杉醇脂质体联合卡铂治疗培美曲塞和顺铂化疗失败的晚期肺腺癌疗效较好,不良反应可耐受.     

Concurrent pemetrexed and radiation therapy in the treatment of patients with inoperable stage III non-small cell lung cancer: A systematic review of completed and ongoing studies

Current standard for locally advanced non-small cell lung cancer (NSCLC) is combined concurrent therapy with a platinum-based regimen. Preclinical synergistic activity of pemetrexed with radiation therapy (RT) and favorable toxicity profile has led to clinical trials evaluating pemetrexed in chemoradiation regimens. This literature search of concurrent pemetrexed and RT treatment of patients with stage III NSCLC included MEDLINE database, meeting abstracts, and the clinical trial registry database. Nineteen unique studies were represented across all databases including 11 phase I studies and eight phase II studies. Of the six phase II trials with mature data available, median overall survival ranged from 18.7 to 34 months. Esophagitis and pneumonitis occurred in 0–16% and 0–23% of patients, respectively. Of the ongoing trials, there is one phase III and four phase II trials with pemetrexed in locally advanced NSCLC. Pemetrexed can be administered safely at full systemic doses with either cisplatin or carboplatin concomitantly with radical doses of thoracic radiation therapy. While results from the ongoing phase III PROCLAIM trial are needed to address definitively the efficacy of pemetrexed–cisplatin plus RT in stage III NSCLC, available results from phase II trials suggest that this regimen has promising activity with an acceptable toxicity profile.     

Pharmacokinetic evaluation of platinum derived from cisplatin administered alone and with pemetrexed in head and neck cancer patients

Purpose  This phase I study characterized the pharmacokinetics of free and total platinum derived from cisplatin administered alone and in combination with pemetrexed. Secondary objectives were to assess the pharmacokinetics of pemetrexed when it is combined with cisplatin as well as to evaluate the safety profile and document antitumor activity associated with this combination. Methods  An open-label, two-arm, cross-over phase 1 study was performed in patients with squamous cell carcinoma of the head and neck, age ≥18 years, an Eastern Cooperative Oncology Group performance status of 0–2, and adequate organ function. Blood samples were taken and pharmacokinetics evaluated for the first two cycles using noncompartmental analysis. Patients received either pemetrexed (500 mg m⁻²) plus cisplatin (75 mg m⁻²) administered in cycle 1 followed by cisplatin alone in cycle 2; or in the reverse order (i.e., cisplatin alone in cycle 1 followed by pemetrexed plus cisplatin in cycle 2). Each treatment cycle was 21 days and patients received folic acid, vitamin B₁₂ supplementation, and dexamethasone prophylaxis. After the first two cycles, patients continued study treatment with pemetrexed plus cisplatin every 3 weeks up to a maximum of six total treatment cycles. Toxicities were graded by the investigators according to the National Cancer Institute Common Toxicity Criteria for Adverse Events (CTCAE), version 3.0. Results  A total of 13 patients were treated; one patient was discontinued from the study after cycle 1 for failure to meet baseline eligibility criteria for renal function. The ratios and 90% confidence intervals (CI) comparing the pharmacokinetics for cisplatin administered with pemetrexed to those for cisplatin administered alone for free platinum were: C _max = 1.08 (CI: 0.92, 1.27) and AUC = 0.93 (CI: 0.82, 1.06); and, total platinum were: C _max = 0.97 (CI: 0.88, 1.06) and AUC = 0.87 (CI: 0.81, 0.93). These results indicate that platinum pharmacokinetics (free and total) are similar, whether cisplatin is administered alone or combined with pemetrexed. The pemetrexed pharmacokinetic results were consistent with those from previous single-agent pemetrexed studies and a previous study of pemetrexed in combination with cisplatin. The combination of pemetrexed and cisplatin did not show any unexpected toxicities. Consistent with the platinum pharmacokinetic results, co-administration with pemetrexed did not appear to enhance cisplatin-related toxicities. Of the 13 treated patients, 11 had stable disease as the best overall response and 2 had progressive disease. Conclusions  The pharmacokinetics of free platinum derived from cisplatin were not altered by co-administration with pemetrexed, and in agreement with this, no unexpected cisplatin-induced toxicities were observed when these drugs were combined.