Second-line Therapy For Small-cell Lung Cancer Research Articles

Second-line lurbinectedin as a new treatment option for small-cell lung cancer: Preliminary results in real-clinical practice.

IntroductionFew strategies exist for treatment of patients with small‐cell lung cancer (SCLC) extended‐stage after failure of first‐line platinum‐based chemotherapy. Lurbinectedin is a novel RNA‐polymerase‐II inhibitor investigated as a second‐line therapy for SCLC. However, its efficacy and safety profile in real clinical practice remain to be determined.ObjectiveTo determine the efficacy and safety of lurbinectedin in real‐life among patients with SCLC previously treated with first‐line platinum‐based chemotherapy.MethodsWe retrospectively evaluated patients who received at least one dose of lurbinectedin (3.2 mg/m2) between March 2020 and November 2021, in the pulmonary department of Bordeaux University Hospital. Endpoints were time to treatment discontinuation, progression‐free survival, overall survival, and safety profile.ResultsThirteen patients were included. The median age was 60 years (range: 42–77), seven (54%) were females, nine (69%) having a performance status of 0–1. Lurbinectedin was given as second‐line treatment before platinum rechallenge in four (31%) patients. After a mean follow‐up of 4.1 months, the objective response rate (ORR) was 17%. The median time to treatment discontinuation (TTD) was 2.3 months (interquartile range [IQR], 1.2–3.6). The median progression‐free survival (PFS) and overall survival (OS) were, respectively, 1.9 (IQR, 0.1.8) and 4.1 (IQR, 2.0–3.5) months. No significant difference regarding TTD, PFS or OS was found in the two groups according to treatment history or according to chemotherapy‐free intervall (CMI) 〈1 or 〉1 month. The most common adverse events (AEs) were asthenia, nausea, and anemia in nine (70%) patients. Grade 3 AEs were reported, fatigue, vomiting, nausea, anorexia, and neutropenia.ConclusionsLurbinectedin in real clinical practice could have had a lower efficacy than in phase II trial, but a better hematological and bioclinical tolerance than previously reported. Early relapse after platinum‐based chemotherapy seems to have a lower response to lurbinectedin.

Efficacy and safety of lurbinectedin and doxorubicin in relapsed small cell lung cancer. Results from an expansion cohort of a phase I study

SummaryBackground A phase I study found remarkable activity and manageable toxicity for doxorubicin (bolus) plus lurbinectedin (1-h intravenous [i.v.] infusion) on Day 1 every three weeks (q3wk) as second-line therapy in relapsed small cell lung cancer (SCLC). An expansion cohort further evaluated this combination. Patients and methods Twenty-eight patients with relapsed SCLC after no more than one line of cytotoxic-containing chemotherapy were treated: 18 (64%) with sensitive disease (chemotherapy-free interval [CTFI] ≥90 days) and ten (36%) with resistant disease (CTFI <90 days; including six with refractory disease [CTFI ≤30 days]). Results Ten patients showed confirmed response (overall response rate [ORR] = 36%); median progression-free survival (PFS) = 3.3 months; median overall survival (OS) = 7.9 months. ORR was 50% in sensitive disease (median PFS = 5.7 months; median OS = 11.5 months) and 10% in resistant disease (median PFS = 1.3 months; median OS = 4.6 months). The main toxicity was transient and reversible myelosuppression. Treatment-related non-hematological events (fatigue, nausea, decreased appetite, vomiting, alopecia) were mostly mild or moderate. Conclusion Doxorubicin 40 mg/m2 and lurbinectedin 2.0 mg/m2 on Day 1 q3wk has shown noteworthy activity in relapsed SCLC and a manageable safety profile. The combination is being evaluated as second-line therapy for SCLC in an ongoing, randomized phase III trial. Clinical trial registrationwww.ClinicalTrials.gov code: NCT01970540. Date of registration: 22 October, 2013.

Lurbinectedin: A New Treatment Option for Relapsed/Refractory Small-Cell Lung Cancer.

To assess the clinical application of lurbinectedin and its role in the therapy of small-cell lung cancer (SCLC). PubMed database and ClincialTrials.gov were utilized to perform a comprehensive literature search from August 2011 to mid-November 2020 with the terms lurbinectedin and PM01183. English-language clinical trials of lurbinectedin were evaluated. Lurbinectedin, as second-line therapy in SCLC, demonstrated an overall response (OR) rate of 35.2% and median overall survival of 9.3 months. Phase II studies in multiple cancers revealed myelosuppression (>95%), increased liver enzymes (>70%), nausea (up to 80%), vomiting (54%), and fatigue (>50%) as the most common adverse events associated with lurbinectedin. CYP3A4 drug interactions affect lurbinectedin exposure (severe pancytopenia occurred after coadministration with aprepitant), and protein binding can affect its clearance. Patients with cardiac comorbidities were not included in published lurbinectedin trials because of cardiotoxicity associated with trabectedin. Lurbinectedin is an option in SCLC after failure of a platinum-based regimen. Dose adjustments, drug interactions, antiemetic regimen choice, and patient comorbidities are important clinical considerations with lurbinectedin use. Likewise, its place in therapy in the era of immune checkpoint inhibitors requires further exploration. With a promising OR compared with other second-line options, lurbinectedin should be considered in patients who have failed first-line therapy. Studies are ongoing with lurbinectedin in combination with other agents in SCLC, and a phase III trial is assessing use in combination with doxorubicin compared with other second-line regimens.

Lurbinectedin as second-line treatment for patients with small-cell lung cancer: a single-arm, open-label, phase 2 basket trial

Few options exist for treatment of patients with small-cell lung cancer (SCLC) after failure of first-line therapy. Lurbinectedin is a selective inhibitor of oncogenic transcription. In this phase 2 study, we evaluated the acti and safety of lurbinectedin in patients with SCLC after failure of platinum-based chemotherapy. In this single-arm, open-label, phase 2 basket trial, we recruited patients from 26 hospitals in six European countries and the USA. Adults (aged ≥18 years) with a pathologically proven diagnosis of SCLC, Eastern Cooperative Oncology Group performance status of 2 or lower, measurable disease as per Response Criteria in Solid Tumors (RECIST) version 1.1, absence of brain metastasis, adequate organ function, and pre-treated with only one previous chemotherapy-containing line of treatment (minimum 3 weeks before study initiation) were eligible. Treatment consisted of 3·2 mg/m2 lurbinectedin administered as a 1-h intravenous infusion every 3 weeks until disease progression or unacceptable toxicity. The primary outcome was the proportion of patients with an overall response (complete or partial response) as assessed by the investigators according to RECIST 1.1. All treated patients were analysed for activity and safety. This study is ongoing and is registered with ClinicalTrials.gov, NCT02454972. Between Oct 16, 2015, and Jan 15, 2019, 105 patients were enrolled and treated with lurbinectedin. Median follow-up was 17·1 months (IQR 6·5-25·3). Overall response by investigator assessment was seen in 37 patients (35·2%; 95% CI 26·2-45·2). The most common grade 3-4 adverse events (irrespective of causality) were haematological abnormalities-namely, anaemia (in nine [9%] patients), leucopenia (30 [29%]), neutropenia (48 [46%]), and thrombocytopenia (seven [7%]). Serious treatment-related adverse events occurred in 11 (10%) patients, of which neutropenia and febrile neutropenia were the most common (five [5%] patients for each). No treatment-related deaths were reported. Lurbinectedin was active as second-line therapy for SCLC in terms of overall response and had an acceptable and manageable safety profile. Lurbinectedin could represent a potential new treatment for patients with SCLC, who have few options especially in the event of a relapse, and is being investigated in combination with doxorubicin as second-line therapy in a randomised phase 3 trial. Pharma Mar.

Advances of second-line therapy for small-cell lung cancer

Small cell lung cancer (SCLC) is a highly malignant tumor, which is very sensitive to first-line chemotherapy, but easy to recurrence and metastasis early. So it always has poor prognosis. Second-line therapy for SCLC develops slowly. Topotecan is the only drug approved by US Food and Drug Administration as a second-line chemoradiotherapy. Numerous studies on molecular targeted therapy and immunotherapy are being carried out, but most of them have no or little benefit. Rovalpituzumab tesirine (Rova-T) targeted antibody-drug conjugate (ADC) which is published at the 2016 American Society of Clinical Oncology Annual Meeting shows a good anti-tumor activity, which seems to bring a new dawn of molecular targeted therapy. Key words: Lung neoplasms; Carcinoma, small cell; Retreatment; Drug therapy

Chemotherapy for Relapsed Small Cell Lung Cancer: A Systematic Review and Practice Guideline

This clinical practice guideline, based on a systematic review, evaluates chemotherapy options for patients with relapsed small cell lung cancer (SCLC). Relevant randomized trials and meta-analyses were identified through a systematic search of the literature. External feedback was obtained from practitioners in Ontario, and the guideline was approved by the provincial lung cancer disease site group. Six randomized trials met the eligibility criteria and were included for review. One randomized phase III trial of oral topotecan versus no treatment in patients receiving best supportive care found topotecan to have a significant benefit in terms of 6-month survival and quality of life. A randomized phase III trial compared outcomes of carboplatin in patients receiving a combination of etoposide and cisplatin (EP) and found no significant improvement associated with carboplatin, although it was associated with significantly higher grade 3/4 thrombocytopenia. Two randomized trials directly compared chemotherapy regimens (intravenous [i.v.] topotecan versus cyclophosphamide, doxorubicin, and vincristine (CAV); and bis-chloro-ethylnitrosourea, thiotepa, vincristine, and cyclophosphamide (BTOC) versus EP), but these trials found no significant differences in terms of disease response or survival. I.v. topotecan was associated with significantly higher toxicities (grade 4 thrombocytopenia and grade 3/4 anemia) and greater improvement in patient-reported symptoms compared with CAV. Two randomized trials of topotecan-treated patients comparing route of administration (i.v. versus oral) found no significant differences in terms of disease response, survival, or quality of life, although oral administration was associated with increased grade 3 or 4 diarrhea in both trials. Evidence on the clinical benefit of second-line therapy in SCLC is limited. Topotecan is the most studied agent in this population; it has a response and survival benefit in comparison with placebo, but it also has greater toxicity in comparison with CAV. To date, significant differences in terms of response and survival are not evident in studied chemotherapy options.

Phase II study of pegylated liposomal doxorubicin HCl (Caelyx) in combination with cyclophosphamide and vincristine as second-line treatment of patients with small cell lung cancer

Despite chemotherapy and radiotherapy for small cell lung cancer (SCLC), most patients die within 2 years. Response rates for second-line chemotherapy are 15-25%, with a median survival of 5 months. Caelyx, a pegylated liposomal formulation of doxorubicin, may be better tolerated and has activity in SCLC. Thirty-two patients were enrolled in a phase II study of intravenous Caelyx (35 mg/m2), cyclophosphamide (750 mg/m2) and vincristine (1.2 mg/m2) every 21 days as second-line therapy in SCLC for up to six cycles. Thirty patients were evaluable for response, with a response rate of 10%. Another two had an unconfirmed response. Stable disease (SD) for >or=2 cycles was seen in an additional 53%. Grade 3 or 4 non-hematologic toxicity was seen in 17 (55%) patients (26 [22%] cycles) and included fatigue, mucositis, plantar-palmar erythrodysesthesia, rash and neuropathy. Twelve patients required transfusions. All patients on study have now expired, with a median survival of 28 weeks (7 months). For patients with SD or partial response, median time to progression was 15 weeks. The combination of Caelyx, cyclophosphamide and vincristine, despite cyclophosphamide and Caelyx dose reductions, has modest activity in relapsed SCLC with acceptable toxicity.

Topotecan and Paclitaxel in Previously Treated Patients with Relapsed Small Cell Lung Cancer: Phase II Trial of the North Central Cancer Treatment Group

Small cell lung cancer (SCLC) is one of the most aggressive and lethal cancers in humans. It constitutes approximately 15 to 25% of all cases of primary lung cancers.1 Initial response rates of 70 to 90% for both limited and extensive stages of SCLC may be achieved using standard combination cytotoxic chemotherapy agents. The 5-year survival for limited-state SCLC is 15 to 25%, but patients with extensivestage SCLC rarely survive 5 years. Even among patients who achieve a complete response, there is a high rate of relapse.2 Until recently, there has been no well-established treatment available for patients with recurrent SCLC.3 Topotecan is a camptothecin analogue that stabilizes the covalent adduct between topoisomerase I and DNA. In S-phase cells, these topo I-DNA adducts are converted into double-strand breaks that seem to be responsible for cytotoxicity.4 Several phase II5–8 trials as well as a phase III trial3 have demonstrated antitumor efficacy, manageable toxicities, and acceptable safety profile of topotecan in both chemo-naive and previously treated patients with SCLC. Patients in the topotecan group derived significant palliative benefits in general symptoms (e.g., anorexia, fatigue, interference with daily activities, and pulmonary symptoms) over CAV chemotherapy in a randomized trial.3 Although topotecan is currently approved for second-line therapy in SCLC at a starting dose of 1.5 mg/m by a daily 30-minute intravenous infusion for 5 consecutive days of a 21-day cycle, advanced age, extensive pretreatment, prior platinum therapy, prior radiotherapy, and renal impairment are potential risk factors for increased myelosuppression during topotecan therapy. Several studies suggest that the 1.0and 1.25-mg/m doses of topotecan may be appropriate for patients with such high-risk factors.9–11 Paclitaxel is a chemotherapeutic agent that promotes the assembly and stabilization of microtubules. Such binding causes cells to form abundant arrays of disorganized and dysfunctional microtubules, leading to apoptosis. Although there is documented single-agent activity of paclitaxel in phase II studies among chemo-naive patients with SCLC with extensive disease,12,13 response duration is short, which suggests that paclitaxel is not sufficient as a single agent. It is also widely accepted that combinations of cytotoxic drugs produce higher response rates and survival rates in patients with SCLC compared with single-agent therapy. The combination of topotecan and paclitaxel is rational as they have non-overlapping mechanisms of action and are both active agents in SCLC, as discussed previously. Moreover, there is demonstrable in vitro synergy of this combination in SCLC cell lines,14,15 although there are insufficient data on sequence-specific synergy. Phase II trials of the combination of topotecan and paclitaxel that have been reported used a 5-day topotecan schedule as first-line treatment in patients with extensive SCLC.16–19 A randomized phase II study evaluating four treatment combinations17 showed that paclitaxel (230 mg/m on day 1) plus topotecan (1 mg/m on days 1-5) produced excessive toxicity, with toxic deaths occurring in 25% of patients. Objective response rate was 54% with a median survival of 13.8 months. The toxicities were ameliorated in the treatment arm using an attenuated paclitaxel dose of 175 mg/m, with treatment-related death occurring in 3% of patients. Objective response rate in this arm was 69% with a median survival of 9.9 months and 1-year survival of 40%, similar to standard etoposide plus cisplatin chemotherapy. Another phase II trial in patients with chemo-naive extensive SCLC used topotecan 1 mg/m (first three patients received 1.25 mg/m) daily for 5 days and paclitaxel (135 mg/m) on day 5 via a 24-hour infusion every 4 weeks.16 Despite prophylactic G-CSF administration, this combination was associated with a high incidence of myelosuppression *Mayo Clinic and Mayo Foundation, Rochester, Minnesota, †Illinois Oncology Research Association CCOP, Peoria, Illinois; ‡Cedar Rapids Oncology Project CCOP, Cedar Rapids, Iowa; §Carle Cancer Center CCOP, Urbana, Illinois; Missouri Valley Cancer Consortium, Omaha, Nebraska; ¶Duluth CCOP, Duluth, Minnesota; **Wichita Community Clinical Oncology Program, Wichita, Kansas; ††Siouxland HematologyOncology Associates, Sioux City, Iowa. Address correspondence to: Grace K. Dy, MD, Mayo Clinic, 200 First Street, SW, Rochester, MN 55905. E-mail: Dy.Grace@mayo.edu Copyright © 2006 by the International Association for the Study of Lung Cancer ISSN: 1556-0864/06/0103-0211

92 CPT 11 (Irinotecan) in pretreated small cell lung cancer (SCLC): A phase II study in patients progressing after a first response (preliminary results)

The standard combination chemotherapy of SCLC is an etoposide based regimen. After failure of this regimen the prognosis is very poor although the use of a rescue regimen still displays clinical activity. It has been already suggested that investigational new drugs should to be assessed in second line therapy in SCLC and that a RR ≥ 10% among 29 patients would be relevant for the screening of active new compounds. CPT11 is a new DNA topoisomerase I inhibitor active in colorectal cancer and other solid adult tumors. 22 patients with progressive extensive SCLC after a prior response on a VP16-based chemotherapy have been so far entered onto the study. Sex ratio M/F = 19/3; median age = 57.2 (43–72). Performance Status 0 = 14%; 1 = 45%; 2 = 41%. Median number of involved organ 4 (1–6) with liver (27%), lung (22%), lymph nodes (16%) and brain (11% of patients). 57 cycles at the planned dose of 350 mg/m 2 every 3 weeks have been delivered with a median Relative Dose Intensity of 0.95 (0.78–1. 03). Efficacy: One CR and three PR have been observed among the 15 evaluable patients. Safety: The incidence of grade 3 and 4 toxicity per cycle has been: neutropenia: 49% (with febrile neutropenia sepsis in 14%), delayed diarrhea: 18%, nausea vomiting: 14%. Conclusion The activity of CPT 11 in SCLC is likely to be attractive on the basis of these preliminary data. Neutropenia is clearly the dose limiting toxicity in this population of pretreated patients with frequent occult bone marrow involvement.