Refractory Small-cell Lung Cancer Patients Research Articles

Clinical predictors of survival in patients with relapsed/refractory small-cell lung cancer treated with checkpoint inhibitors: a German multicentric real-world analysis.

Objectives:Small-cell lung cancer (SCLC) is a lung malignancy with high relapse rates and poor survival outcomes. Treatment-resistant disease relapse occurs frequently and effective salvage therapies are urgently needed.Materials and Methods:We aimed to define efficacy and safety of checkpoint inhibitors (CPIs) in a heterogeneous population of relapsed and refractory SCLC patients in a large retrospective multicentric real-world cohort across German tertiary care centers.Results:A total of 111 patients from 11 treatment centers were included. Median age of all patients was 64 years, and 63% were male. Approximately one-third of all patients had poor performance status [Eastern Cooperative Oncology Group (ECOG) ⩾ 2], and 37% had known brain metastases. Patients were heavily pretreated with a median number of prior therapy lines of 2 (range, 1–8). Median follow-up of the entire cohort was 21.7 months. Nivolumab and Nivolumab/Ipilimumab were the most common regimens. Overall disease control rate was 27.2% in all patients and was numerically higher in CPI combination regimens compared with single-agent CPI (31.8% versus 23.8%; p = 0.16). Median overall survival (OS) was 5.8 months [95% confidence interval (CI), 1.7–9.9 months]. The 12- and 24-month survival rates were 31.8% and 12.7%, respectively. The 12-week death rate was 27.9%. Disease control and response rate were significantly lower in patients with liver metastases. Platinum sensitivity (to first-line treatment), metastatic burden, and lactate dehydrogenase (LDH) showed prognostic impact on survival in univariate analysis. Neutrophil-to-lymphocyte ratio (NLR) was a significant and independent predictor of survival in univariate (p = 0.01) and multivariate analyses [hazard ratio (HR), 2.1; 95% CI = 1.1–4.1; p = 0.03].Conclusion:CPI in patients with relapsed or refractory (R/R) SCLC is of limited value in an overall patient cohort; however, long-term survival, in particular with CPI combination strategies, is possible. Clinical characteristics allow a more differentiated subgroup selection, in particular patients with low NLR showed less benefit from CPI in R/R SCLC.

Post-progression survival is strongly linked to overall survival in refractory small-cell lung cancer patients who received amrubicin.

The benefits of second-line chemotherapy on the overall survival (OS) of small-cell lung cancer (SCLC) patients might be confounded by subsequent therapies. In this study, we aimed to determine the influence of progression-free survival (PFS) and postprogression survival (PPS) on OS after second-line chemotherapy in patients with refractory SCLC treated with amrubicin monotherapy. We analyzed the data of 35 patients with refractory SCLC who were treated with amrubicin monotherapy as second-line chemotherapy between July 2005 and December 2015. The correlations of PFS and PPS with OS were statistically analyzed at the individual level using Spearman's rank correlation and linear regression analyses. The correlation between PPS and OS was strong (r = 0.88, P < 0.05, R2 = 0.87), while that between PFS and OS was weak (r = 0.60, P < 0.05, R2 = 0.15). The number of regimens administered after disease progression postsecond-line chemotherapy was significantly associated with PPS (P = 0.003). OS is more strongly linked to PPS than to PFS in refractory SCLC patients who undergo amrubicin monotherapy as a second-line treatment. These results suggest that treatments administered after second-line chemotherapy affect the OS of refractory SCLC patients treated with amrubicin monotherapy.

P2.15-005 Post-Progression Survival Is Strongly Linked to Overall Survival in Refractory Small-Cell Lung Cancer Patients Who Received Amrubicin

P2.15-005 Post-Progression Survival Is Strongly Linked to Overall Survival in Refractory Small-Cell Lung Cancer Patients Who Received Amrubicin

A Systematic Analysis of Efficacy of Second-Line Chemotherapy in Sensitive and Refractory Small-Cell Lung Cancer

Small-cell lung cancer (SCLC) patients unresponsive or relapsing within 90 days after frontline chemotherapy have poor prognosis and are treated with regimens different from the first-line regimen. Potential differences in the efficacy of second-line therapy for refractory and sensitive SCLC have not been well studied. Studies that enrolled sensitive and refractory (relapse < 90 days or > 90 days) SCLC patients for second-line therapy were identified using electronic databases (MEDLINE, EMBASE, and Cochrane library), and meeting abstracts databases. A systematic analysis was conducted using Comprehensive Meta Analysis (version 2.2.048) software to calculate the odds ratio of response and 95% confidence interval. Median overall survival time for sensitive and resistant SCLC patients was compared by two-sided Student's t test. We tested for significant heterogeneity by Cochran's chi-square test and I-square index. Twenty-one studies published between 1984 and 2011 were eligible for this analysis with a total of 1692 patients enrolled; 912 with sensitive and 780 with refractory SCLC. The overall response rate was 17.9% with a higher response rate of 27.7% (range, 0%-77%) for sensitive SCLC versus 14.8% (range, 0%-70%) for refractory patients; p=0.0001. Pooled overall odds ratio of response was 2.235 (95% confidence interval: 1.518-3.291; p=0.001) favoring patients with sensitive disease. Median overall survival time was 6.7 months with a weighted survival of 7.7 and 5.4 months for sensitive and refractory SCLC, respectively (p = 0.0035). Refractory SCLC patients derive modest clinical benefit from second-line chemotherapy. However, response and survival outcomes are superior with chemosensitive disease.

Immunological evaluation of personalized peptide vaccination in refractory small cell lung cancer

Since the prognosis of small cell lung cancer (SCLC) remains poor, development of new therapeutic approaches, including immunotherapies, would be desirable. In the current study, to evaluate immunological responses in refractory SCLC patients, we conducted a small scale phase II clinical trial of personalized peptide vaccination (PPV), in which vaccine antigens are selected based on pre-existing host immunity. Ten refractory SCLC patients, who had failed to respond to chemo- and/or chemoradiotherapies (median number of regimens, 2.5; median duration, 20.5 months), were enrolled. A maximum of four human leukocyte antigen (HLA)-matched peptides showing higher antigen-specific humoral responses were subcutaneously administered (weekly for six consecutive weeks and then bi-weekly thereafter). PPV was terminated before the 3rd administration in four patients because of rapid disease progression, whereas the remaining six patients completed at least one cycle (six times) of vaccinations. Peptide-specific immunological boosting was observed in all of the six patients at the end of the first cycle of vaccinations, with their survival time of 25, 24.5 (alive), 10 (alive), 9.5, 6.5, and 6 months. Number of previous chemotherapy regimens and frequency of CD3(+) CD26(+) cells in peripheral blood were potentially prognostic in the vaccinated patients (hazard ratio [HR] = 2.540, 95% confidence interval [CI] = 1.188-5.431, P = 0.016; HR = 0.941, 95% CI = 0.878-1.008, P = 0.084; respectively). Based on the feasible immune responses in refractory SCLC patients who received at least one cycle (six times) of vaccinations, PPV could be recommended for a next stage of larger-scale, prospective clinical trials.

A phase II trial of VNP40101M in patients with relapsed or refractory small cell lung cancer (SCLC) with or without brain metastases

7724 Background: Relapsed or refractory SCLC patients (pts) have a poor prognosis. Median survival at relapse is 2–3 months; brain metastases (mets) are common. Alkylating agents have demonstrated activity in SCLC. Cloretazine is a new alkylator that is active against selected alkylating agent resistant tumor cell lines. Xenograft models show distribution across the blood-brain barrier. This study investigates VNP40101M safety and activity in SCLC patients who have relapsed or are refractory to standard 1st line chemotherapy. Methods: Pts are entered in 2 groups based on response to prior chemotherapy: sensitive relapse (chemotherapy-free interval &gt;3 months); or resistant/refractory (chemotherapy-free interval ≤3 months). Eligibility criteria include: measurable or evaluable disease; life expectancy of ≥2 months; and ECOG PS of 0–2. Pts with brain mets are eligible. 31 pts received VNP40101M IV at a starting dose of 125 mg/m2/wk × 3, every 6 weeks. Due to a high incidence of grade 3–4 thrombocytopenia (34%), an amended protocol reduced the dose of VNP40101M to 100 mg/m2 at the same schedule. 13 pts received the reduced dose. Pts are evaluated by RECIST criteria after each 6-week cycle. Results: 44 of 87 planned pts have been treated at 7 sites. Of 41 evaluable pts, 21 patients have sensitive relapse disease, and 20 have resistant/refractory disease. Median age is 64 years (44–86). Median number of cycles received is 1 (1–3). Grade 3–4 thrombocytopenia was seen in 11/31 pts at the 125 mg/m2 dose and 3/13 pts at the 100 mg/m2 dose. Gr 3–4 non-hematologic toxicity is rare, except for fatigue (10%) and GI effects (10%). The response rate (PR) is 6/21 (29%) in the sensitive relapse group, and 1/20 (5%) in the resistant/refractory group. 2/6 PRs, in the sensitive relapse group, occurred at the reduced dose level. 16 pts had brain mets at study entry. Of these, there were 3 PRs (2 with measurable regression of brain mets) and 3 stable diseases. Conclusions: The study is ongoing to confirm efficacy and safety. VNP40101M has activity against SCLC in the 2nd line setting including pts with brain metastases; further study is warranted. No significant financial relationships to disclose.

Phase II trial of irinotecan/gemcitabine as second-line therapy for relapsed and refractory small-cell lung cancer: Cancer and Leukemia Group B Study 39902

This phase II study evaluated the efficacy and safety of the irinotecan/gemcitabine combination in patients with relapsed/refractory small-cell lung cancer (SCLC). Patients with measurable tumor who had received one previous chemotherapy or chemotherapy/radiation regimen were eligible. Gemcitabine 1000 mg/m(2) was administered i.v. over 30 min followed immediately by irinotecan 100 mg/m(2) i.v. over 90 min, both on days 1 and 8 every 21 days. Patients were stratified based on response to initial treatment [i.e. primary sensitive disease with progression >or=3 months (group A), or refractory disease (group B)]. Seventy-three patients were enrolled but one never received treatment and one ineligible patient did not have SCLC. Median patient ages of the remaining patients were 61 and 63 years in groups A (n = 35) and B (n = 36), respectively, with performance status of 0 or 1 in 85% of 71 patients. Primary grade 3/4 toxic effects in groups A versus B were neutropenia (36% versus 43%), thrombocytopenia (36% versus 26%), nausea (12% versus 11%), vomiting (0 versus 11%), diarrhea (12% versus 9%), and pulmonary (12% versus 12%). Two patients had fatal events including pneumonitis (n = 1) and acute respiratory distress syndrome (n = 1). Responses occurred in 11 group A [two complete responses and nine partial responses (PRs)] and four group B (all PRs) patients, for response rates of 31% [95% confidence interval (CI) 17%, 49%) and 11% (95% CI 3%, 26%), respectively. Median survival and progression-free survival times were 7.1 (95% CI 6, 10.5) versus 3.5 (95% CI 3.1, 5.7) months, and 3.1 (95% CI 1.6, 5.3) versus 1.6 (95% CI 1.4, 2.8) months for group A versus B. The irinotecan/gemcitabine combination is active and well tolerated as second-line therapy in SCLC patients. Additional studies are warranted as second-line therapy in patients who progressed 90 days or more after first-line therapy. However, the observed efficacy results in refractory SCLC patients indicate that this regimen should not be further explored in this population.

Effects of the 26S proteasome inhibitor, bortezomib, on BCL-2 in small cell lung cancer: Implications for SWOG-0327

9560 Background: Overexpression of the anti-apoptotic protein BCL-2 is seen in approximately 80% of small cell lung cancer (SCLC) and has been associated with chemoresistance and poor prognosis. We have previously shown that the the serine protein kinase AKT signals through the transcriptional factor NF-kB to increase BCL-2 levels and that inhibition of NF-kB activity with the 26S proteasome inhibitor bortezomib decreases BCL-2 levels and induces apoptosis in a pancreatic cancer model. We tested the hypothesis that the AKT/NF-kB signaling pathway is involved in the overexpression of BCL-2 in SCLC, and whether inhibition of NF-kB through 26S proteasome inhibition with bortezomib would decrease BCL-2 levels. Methods: The H526 human SCLC line was used for all studies. The activity of the BCL-2 promoter was determined by promoter/luciferase reporter constructs following transient transfection. Similarly, NF-kB function was determined following transient transfection of a luciferase reporter construct containing four tandem NF-kB sites as a minimal promoter. Western blot analysis was used to evaluate protein levels and modifications of BCL-2. Results: Constitutive activation of AKT through transfection of a myrstilated form had no effect on BCL-2 levels in H526 cells, nor did it alter NF-kB activity. However, mutation of a NF-kB site in the BCL-2 promoter reduced BCL-2 promoter activity to less than 25% of the wild-type promoter. Treatment of H526 cells with bortezomib decreased BCL-2 protein levels, as well as induced inactivation of BCL-2 by phosphorylation and increased degradation. Conclusions: BCL-2 overexpression in H526 SCLC cells is not mediated by activation of AKT, though NF-kB plays a major role in transcriptional activation. Treatment with the 26S proteasome inhibitor bortezomib has effects on BCL-2 transcription, likely through inhibition of NF-kB, as well as effects involving BCL-2 inactivation through protein modification.These data provide the preclinical basis for SWOG-0327, an ongoing phase II trial of bortezomib in relapsed refractory SCLC patients. (CA 32102, CA 62505) No significant financial relationships to disclose.

Phase II Study of Topotecan and Etoposide as Second-line Treatment in Chemotherapy-refractory Small-cell Lung Cancer.

Refractory small-cell lung cancer (SCLC) has a poor prognosis, and current salvage chemotherapy for refractory SCLC, such as CAV (cyclophosphamide, adriamycin, vincristine) or topotecan, has an unsatisfactory outcome, with a response rate and overall survival of less than 10% and 6 months, respectively. This phase II study evaluated the role of topotecan combined with etoposide in SCLC patients that have progressed, or relapsed, within 3 months following completion of the initial chemotherapy. Twenty-seven patients were entered into this study. Eligible patients had an ECOG performance status of less than, or equal to, 2, at least one bidimensionally measurable lesion and adequate end organ function. IV topotecan, 1.0 mg/m2/d for 5 consecutive days, and etoposide, 100 mg/m2/d through days 1 to 3, were administered every 3 weeks until disease progression or undue toxicity. The major toxicity was myelosuppression. Grade 3/4 anemia, granulocytopenia, and thrombocy-topenia occurred in 14.2, 34.8, and 27.3% of cycles, respectively. There was no treatment-related death, and other non-hematologic toxicities were generally mild. Four patients achieved partial responses, with a response rate RR of 14.8%. The progression-free survival PFS ranged from 1 to 7 months, with a median of 2.0 months (95% confidence interval 1.22~2.78 months). Twenty-five patients died, with a median overall survival of 5.5 months (ranging from 1 to 21 months, 95% CI 4.32~6.68 months), and the 6-month survival rate was 32.1% (95% confidence interval 14.4~49.8%). The combination of topotecan and etoposide chemotherapy showed a modest response rate, but failed to prolong survival of refractory SCLC patients compared to topotecan monotherapy.

A new quinoline derivative MS-209 reverses multidrug resistance and inhibits multiorgan metastases by P-glycoprotein-expressing human small cell lung cancer cells.

Development of distant metastases and acquired multidrug resistance (MDR) are major problems in therapy for human small cell lung cancer (SCLC). MS‐209 is a novel quinoline compound, which reverses P‐glycoprotein (P‐gp)‐mediated MDR. We previously reported that MS‐209 reversed in vitro MDR of human SCLC (SBC‐3/ADM and H69/VP) cells expressing P‐gp. In the present study, we determined the therapeutic effect of MS‐209 in combination with chemotherapy against multiorgan metastases of MDR SCLC cells. SBC‐3/ADM cells expressing P‐gp were highly resistant to etoposide (VP‐16), adriamycin (ADM), and vincristine (VCR) in vitro, compared with parental SBC‐3 cells lacking P‐gp expression. MS‐209 restored chemosensitivity of SBC‐3/ADM cells to VP‐16, ADM, and VCR in a dose‐dependent manner in vitro. Intravenous injection with SBC‐3 or SBC‐3/ADM cells produced metastatic colonies in the liver, kidneys and lymph nodes in natural killer (NK) cell‐depleted severe combined immunodeficiency (SCID) mice, though SBC‐3/ ADM cells more rapidly produced metastases than did SBC‐3 cells. Treatment with VP‐16 and ADM reduced metastasis formation by SBC‐3 cells, whereas the same treatment did not affect metastasis by SBC‐3/ADM cells. Although MS‐209 alone had no effect on metastasis by SBC‐3 or SBC‐3/ADM cells, combined use of MS‐209 with VP‐16 or ADM resulted in marked inhibition of metastasis formation by SBC‐3/ADM cells to multiple organs. These findings suggest that MS‐209 reversed the MDR of SBC‐3/ADM cells, but not SBC‐3 cells, growing in the various organs, and inhibited metastasis formation in vivo. Therefore, this chemosensitizing agent, MS‐209, may be useful for treatment of refractory SCLC patients with multiorgan metastases.