A Phase II Study with Teniposide (VM26) in Patients with Progressed or Relapsed Small Cell Lung Cancer (SCLC)

Summary

Sixteen patients with advanced small cell lung cancer who relapsed or progressed under first-line therapy, were treated with second-line chemotherapy consisting of: teniposide, 60 mg/m², i.v. days 1-5, every 3 weeks until further progression.

The response rate was: 3 minor responses, 6 stable disease, 5 progressive disease, 1 early death and 1 not evaluable. After the introduction of teniposide, median survival was 4.5 (range 1-11) months, compared to the median survival (2 months, range 1-11) observed in 40 contemporary patients of our series, who relapsed or progressed and subsequently received no treatment. The assessment of the difference was significant: chi-square = 4.05, P<0.05. In addition a particular comparison was performed with 15/40 patients who matched according to the major predictive parameters of disease. These patients experienced 2 months (range 1-7) of median survival which was significantly shorter than that of the teniposide treated group (chi-square = 4.48, P< 0.05). On these bases, teniposide appeared to be effective, but the small size of the study suggests caution in evaluating the results.     

Brief Report: Exploratory Analysis of Maintenance Therapy in Patients With Extensive-Stage SCLC Treated First Line With Atezolizumab Plus Carboplatin and Etoposide

IntroductionIn the phase 1/3 IMpower133 study, atezolizumab plus carboplatin and etoposide (CP/ET) followed by maintenance atezolizumab for first-line treatment of extensive-stage SCLC (ES-SCLC) led to improvement in both overall survival (OS) and progression-free survival (PFS) versus placebo plus CP/ET followed by maintenance placebo. We explored the benefit of atezolizumab versus placebo in the subset of patients who reached the IMpower133 maintenance phase and the safety profile of maintenance therapy.MethodsPatients with untreated ES-SCLC were randomized 1:1 to four 21-day cycles of CP/ET with atezolizumab or placebo, followed by maintenance atezolizumab or placebo. The primary end points were OS and investigator-assessed PFS. A multivariate Cox model from the start of maintenance treatment was used to evaluate the treatment effect and account for lead-time bias; a generalized linear model was used to identify prognostic or predictive characteristics for reaching the maintenance phase.ResultsA similar proportion of patients in each arm received at least the first dose of maintenance therapy (atezolizumab: 77%, n = 154 of 201; placebo: 81%, n = 164 of 202) and were included in the maintenance analysis population. An Eastern Cooperative Oncology Group performance status of 0 and absence of liver metastases at baseline were identified as prognostic factors for reaching the maintenance phase. The positive treatment effect with atezolizumab remained after adjusting for baseline characteristics. Median OS and PFS from the start of maintenance therapy in the atezolizumab versus placebo arm were 12.5 versus 8.4 months (hazard ratio = 0.59, 95% confidence interval: 0.43–0.80) and 2.6 versus 1.8 months (hazard ratio = 0.63 [95% confidence interval: 0.49–0.80]), respectively. Treatment-related adverse events from the start of maintenance therapy occurred in 41% (n = 64 of 155) and 25% (n = 41 of 163) of safety-evaluable patients in the atezolizumab and placebo arms, respectively, and were grade 3 or 4 in 28% (n = 43 of 155) and 23% (n = 37 of 163) of the respective populations; no patient in the atezolizumab arm and one patient in the placebo arm had a grade 5 treatment-related adverse event.ConclusionsThese data in the context of other immunotherapy trials in ES-SCLC suggest that induction with atezolizumab plus CP/ET and maintenance treatment with atezolizumab are important components that contributed to the OS benefit observed in IMpower133. Safety results from randomization and from the start of maintenance therapy were similar between the treatment arms despite the continuation of atezolizumab in the maintenance phase.     

Phase I Trial of Pembrolizumab and Radiation Therapy after Induction Chemotherapy for Extensive-Stage Small Cell Lung Cancer

IntruductionRadiation and immunotherapy have separately been shown to confer survival advantages to patients with extensive-stage small cell lung cancer (ESCLC), but failure rates remain high and combination therapy has been understudied. In this single-arm phase I trial (NCT02402920), we assessed the safety of combining pembrolizumab with thoracic radiotherapy (TRT) after induction chemotherapy for SCLC.MethodsPatients with ESCLC who had completed chemotherapy received TRT with pembrolizumab. The maximum tolerated dose of pembrolizumab was assessed by 3+3 dose-escalation; doses began at 100 mg and increased in 50 mg increments to 200 mg. Pembrolizumab was given every 3 weeks for up to 16 cycles; TRT was prescribed as 45 Gy in 15 daily fractions. Toxicity was evaluated with the Common Terminology Criteria for Adverse Events v4.0. The primary endpoint was safety of the combined therapy based on the incidence of dose-limiting toxicity in the 35 days following initiation of treatment.ResultsThirty-eight patients with ESCLC (median age 65 years, range: 37–79 years) were enrolled from September 2015 through September 2017; 33 received per-protocol treatment, and all tolerated pembrolizumab at 100 to 200 mg with no dose-limiting toxicity in the 35-day window. There were no grade 4-5 toxicities; 2 (6%) patients experienced grade 3 events (n = 1 rash, n = 1 asthenia/paresthesia/autoimmune disorder) that were unlikely/doubtfully related to protocol therapy. The median follow-up time was 7.3 months (range: 1–13 months); median progression-free and overall survival times were 6.1 months (95% confidence interval: 4.1–8.1) and 8.4 months (95% confidence interval: 6.7-10.1).ConclusionsConcurrent pembrolizumab-TRT was tolerated well with few high-grade adverse events in the short-term; progression-free and overall survival rates are difficult to interpret due to heterogeneity in eligibility criteria (e.g., enrolling progressors on induction chemotherapy). Although randomized studies have shown benefits to TRT alone and immunotherapy alone, the safety of the combined regimen supports further investigation as a foundational approach for future prospective studies.     

Immunotherapy in Extensive-Stage Small Cell Lung Cancer

Small cell lung cancer (SCLC) remains a poorly understood disease with aggressive features, high relapse rates, and significant morbidity as well as mortality, yet persistently limited treatment options. For three decades, the treatment algorithm of SCLC has been stagnant despite multiple attempts to find alternative therapeutic options that could improve responses and increase survival rates. On the other hand, immunotherapy has been a thriving concept that revolutionized treatment options in multiple malignancies, rendering previously untreatable diseases potentially curable. In extensive stage SCLC, immunotherapy significantly altered the course of disease and is now part of the treatment algorithm in the first-line setting. Nevertheless, the important questions that arise are how best to implement immunotherapy, who would benefit the most, and finally, how to enhance responses.     

Pembrolizumab After Two or More Lines of Previous Therapy in Patients With Recurrent or Metastatic SCLC: Results From the KEYNOTE-028 and KEYNOTE-158 Studies

IntroductionPembrolizumab has shown clinical benefit in patients with previously treated recurrent or metastatic SCLC in the phase 1b multicohort study KEYNOTE-028 (NCT02054806) and the phase 2 multicohort study KEYNOTE-158 (NCT02628067). We present a pooled analysis of patients from KEYNOTE-028 and KEYNOTE-158 who had received two or more lines of previous therapy for SCLC.MethodsEligible patients were aged 18 years and above, had histologically or cytologically confirmed incurable recurrent or metastatic SCLC, had an Eastern Cooperative Oncology Group performance status of 1 and below, and had received two or more lines of previous therapy. Patients in KEYNOTE-028 were required to have a programmed death ligand 1 (PD-L1)–positive tumor. Patients received pembrolizumab (10 mg/kg every 2 weeks in KEYNOTE-028 or 200 mg every 3 weeks in KEYNOTE-158) for up to 2 years. The primary end point was objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1, which is presented here per independent review.ResultsEighty-three patients who had received two or more lines of previous therapy (KEYNOTE-028, n = 19; KEYNOTE-158, n = 64) were included. Median follow-up duration was 7.7 (range, 0.5–48.7) months. Objective response rate was 19.3% (95% confidence interval: 11.4–29.4); two patients had complete response (one with a PD-L1–positive tumor), and 14 patients had partial response (13 with PD-L1–positive tumors). The median duration of response was not reached (range, 4.1‒35.8+ mo; plus sign indicates ongoing response); 61% of responders had responses lasting 18 months or longer. Fifty-one patients (61.4%) experienced any-grade treatment-related adverse events; eight patients (9.6%) had grade 3 or higher events.ConclusionsPembrolizumab exhibited durable antitumor activity in a subset of patients with recurrent or metastatic SCLC who had undergone two or more previous lines of therapy, regardless of PD-L1 expression. Pembrolizumab was well tolerated.     

Asymptomatic Brain Metastases (BM) in Small Cell Lung Cancer (SCLC): MR-imaging is Useful at Initial Diagnosis

Purpose. In this study we evaluated the usefulness of MR-imaging in the detection of asymptomatic brain metastases (BM) at the initial diagnosis in patients with small cell lung cancer (SCLC) and studied the follow-up of these patients. Patients and methods. One-hundred and twenty-five patients with SCLC were investigated with MR-imaging. Results. In 112 patients with normal neurological findings, MR-imaging of the brain demonstrated BM in 17 patients (15%). Six of these 17 patients were therefore upgraded to extensive disease (ED). Two of these 17 patients died during chemotherapy because of progressive disease and 3 patients became neurologic symptomatic with progressive disease on MR-imaging of the brain. After completion of chemotherapy a repeated MR-imaging of the brain in the remaining 12 patients showed 1 complete remission, 4 partial remission and 7 progressive disease of the BM. Conclusion. This study showed that at presentation an unexpectedly high percentage of SCLC patients had asymptomatic BM on MR-imaging. We propose that MR-imaging of the brain should be included in the staging of SCLC patients as well for staging, prognosis and therapy.     

化疗相关性白细胞减少等因素对小细胞肺癌生存期的影响

目的 探讨影响小细胞肺癌（small cell lung cancer,SCLC）患者生存期的因素。方法 回顾性研究123例SCLC患者的临床资料,利用SPSS15.0统计软件Cox回归模型分析性别、年龄、吸烟、合并症、临床分期、ECOG评分、治疗方法、CEA、化疗相关性白细胞减少（chemotherapy induced leucopenia,CIL ）9个预后因素对生存期的影响。结果随访1～52月,死亡103例。6月、1年、2年、3年、4年存活率分别为70.7%、34.1%、8.94%、2.4%、0.8%,中位生存期11月[95%CI(9.328, 12.627)]。Cox回归多因素分析显示,影响预后的独立因素是：ECOG评分（P=0.000）、化疗联合放疗（P=0.000）、临床分期（P=0.024）、CIL(P=0.013)。结论临床分期早、ECOG评分低、接受化疗联合放疗且出现CIL的SCLC患者生存期长、预后好。     

Phase II Study of Carboplatin in Small Cell Lung Cancer

Carboplatin (CBDCA; cis-diammine-1, 1-cyclobutane dicarboxylateplatinum II), a new platinum analogue, was administered to 18patients with small cell lung cancer (SCLC) at a dose of 300–450mg/m² intravenously every four weeks, in a phase II study. Allpatients could be evaluated to assess response and 17 for toxicity.The overall response rate was 28% (5/18), including one completeresponse. Of eight patients previously untreated, four (50%)showed a response, including one complete response. The responserate in patients with no previous cisplatintreatment was 50%(5/10). Response durations in five responders were 2, 3, >4,> 10 and 11 months. Toxicity was primarily hematologic,with thrombocytopenia being dose-limiting. Thrombocytopenia(<75,000/mm³) was observed in 12 patients (71%), six requiringplatelet transfusion. Leukopenia (<3,000/mm³) was observedin 11 patients (65%). There were no episodes of serious infectionor bleeding, however. Myelosuppression was more severe in heavilypretreated patients than in patients previously untreated. Dosereductions were required following multiple treatments for cumulativemyelotoxicity. Mild to moderate nausea and vomiting occurredin seven patients (44%). Nephrotoxicity and ototoxicity werenot observed. Carboplatin was demonstrated to be an active agentagainst SCLC. Further investigation into dose and schedule ofCBDCA in combination chemotherapy is warranted.     

小细胞肺癌组织中p53基因改变的研究

为探讨小细胞肺癌（ＳＣＬＣ）发生的分子机制，应用免疫组化和聚合酶链反应—单链构象多态性分析的方法，对１４例ＳＣＬＣ组织进行ｐ５３基因突变研究。结果显示，有９例出现ｐ５３蛋白阳性，阳性率为６４．３％（９／１４）。ｐ５３基因第５，６，７，８外显子突变率分别为２１．４％（３／１４），１４．３％（２／１４），１４．３％（２／１４），７．１％（１／１４），总突变率为５７．１％（８／１４）。结果表明，ＳＣＬＣ组织中存在较高的ｐ５３基因突变率，故ｐ５３基因可能是人类肺癌发生的关键基因。     

人小细胞肺癌P^53基因突变的研究

为探讨小细胞肺癌（SCLC）发生的分子机制，应用免疫组化和聚合酶链反应─-单链构象多态性（PCR－SSCP）技术，对14例SCLC的石蜡切片标本进行了P53基因突变研究。结果显示：P53蛋白免疫组织化学反应有9例出现阳性，其中2例为十，7例为～，阳性率为64．3％（9／14）。P53基因第5、6、7、8外显子突变率分别为21．4％（3／14）；14，3％（2／14）;14．3％（2／14）；7．1％（1／14），总突变率为57．1％（8／14）。提示：SCLC中存在较高的P53基因突变率，P53基因突变在人类肺癌的发生发展过程中起着重要的作用。     

Camrelizumab Plus Apatinib in Extensive-Stage SCLC (PASSION): A Multicenter,Two-Stage,Phase 2 Trial

IntroductionTreatment options in the second-line extensive-stage SCLC (ED-SCLC) setting are limited. The PASSION study (ClinicalTrials.gov identifier: NCT03417895) was a phase 2 study of camrelizumab plus apatinib in ED-SCLC after platinum-based chemotherapy.MethodsIn stage I of the study, patients were randomized (1:1:1) to receive camrelizumab 200 mg every 2 weeks plus apatinib 375 mg once daily (QD), 5 days on and 2 days off, or 7 days on and 7 days off (six patients each cohort). On the basis of tolerability during the first 28-day cycle and efficacy data at stage I, one cohort was chosen to expand to 45 patients at stage II. The primary end point was objective response rate (ORR).ResultsFrom April 20, 2018 to March 12, 2019, a total of 59 patients were enrolled, with 47 patients in the QD cohort. In the QD cohort, confirmed ORR reached 34.0% (95% confidence interval: 20.9‒49.3), the median progression-free survival was 3.6 months, and the median overall survival was 8.4 months. Chemotherapy-sensitive and chemotherapy-resistant patients (defined as patients with disease relapse at ≥90 and <90 d after platinum-based chemotherapy, respectively) had comparable confirmed ORR (37.5% versus 32.3%), median progression-free survival (3.6 versus 2.7 mo), and median overall survival (9.6 versus 8.0 mo). Treatment-related adverse events of grade 3 or higher were reported in 43 of 59 patients (72.9%). Five patients (8.5%) discontinued because of treatment-related adverse events.ConclusionsCamrelizumab plus apatinib exhibited potential antitumor activity in patients with both chemotherapy-sensitive and chemotherapy-resistant ED-SCLC who had failed platinum-based chemotherapy with an acceptable toxicity profile. This phase 2 data warrant further clinical studies of camrelizumab plus apatinib in SCLC.     

A Phase II Trial of Prexasertib (LY2606368) in Patients With Extensive-Stage Small-Cell Lung Cancer

BackgroundThis study assessed the checkpoint kinase 1 inhibitor prexasertib in patients with extensive-stage small-cell lung cancer (ED-SCLC).Patients and MethodsThis was a parallel-cohort phase II study of 105 mg/m² prexasertib once every 14 days for patients who progressed after no more than two prior therapies and had platinum-sensitive (Cohort 1) or platinum-resistant/platinum-refractory (Cohort 2) disease. The primary endpoint was objective response rate (ORR). Secondary endpoints included disease control rate (DCR), progression-free survival (PFS), overall survival (OS), safety, and pharmacokinetics. Exploratory endpoints included biomarker identification and assessment of an alternative regimen (Cohort 3: 40 mg/m² days 1-3, 14-day cycle).ResultsIn Cohort 1 (n = 58), ORR was 5.2%; DCR, 31%; median PFS, 1.41 months (95% confidence interval [CI], 1.31-1.64); and median OS, 5.42 months (95% CI, 3.75-8.51). In Cohort 2 (n = 60), ORR was 0%; DCR, 20%; median PFS, 1.36 months (95% CI, 1.25-1.45); and median OS, 3.15 months (95% CI, 2.27-5.52). The most frequent all-grade, related, treatment-emergent adverse events were decreased neutrophil count (Cohort 1, 69.6%; Cohort 2, 73.3%), decreased platelet count (Cohort 1, 51.8%; Cohort 2, 50.0%), decreased white blood cell count (Cohort 1, 28.6%; Cohort 2, 40.0%), and anemia (Cohort 1, 39.3%; Cohort 2, 28.3%). Eleven patients (19.6%) in Cohort 1 and one patient (1.7%) in Cohort 2 experienced grade ≥3 febrile neutropenia. Prexasertib pharmacokinetics were consistent with prior studies. Cohort 3 outcomes were similar to those of Cohorts 1 and 2. No actionable biomarkers were identified.ConclusionPrexasertib did not demonstrate activity to warrant future development as monotherapy in ED-SCLC.