Consideration of Surrogate Endpoints for Overall Survival Associated With First-Line Immunotherapy in Extensive-Stage Small Cell Lung Cancer

BackgroundThe combination of immune checkpoint inhibitors (ICIs) and chemotherapy is known to improve overall survival (OS) in patients with extensive-stage small cell lung cancer (ES-SCLC). ICIs have different response patterns and survival kinetics characteristics from those of the traditional chemotherapy. In first-line treatment for ES-SCLC, there is an urgent need for surrogate endpoints for the early and accurate prediction of OS. This study aimed to assess progression-free survival (PFS), milestone OS rate, milestone restricted mean survival time (RMST), overall response rate (ORR), and disease control rate (DCR) as proposed surrogate endpoints for OS in ES-SCLC for first-line immunotherapy trials.MethodsBetween January 1, 2013, and December 2020, published articles on randomized clinical trials of ICIs plus chemotherapy in patients with ES-SCLC as first-line therapy were searched in PubMed. Abstracts from the ESMO, ASCO, and WCLC, reported from 2018 onwards, were also searched. A weighted regression analysis based on the weighted least squares method was performed on log-transformed estimates of treatment effect, and the determination coefficient (R2) was calculated to evaluate the association between treatment effect on the surrogate endpoint and OS.ResultsSeven trials, representing 3,009 patients, were included to make up a total of 16 analyzed arms. The ratio of the 12-month OS milestone rate (r = −0.790, P = 0.011, R2 = 0.717) and 12-month OS milestone RMST (r = 0.798, P = 0.010, R2 = 0.702) was strongly correlated with the hazard ratio (HR) for OS. The strongest association was observed between the ratio of the 24-month OS milestone RMST and the HR for OS (r = 0.922, P = 0.001, R2 = 0.825). No associations were observed between the HR for OS and PFS and the RR for ORR and DCR.ConclusionsThe results suggested a strong correlation among the ratio of OS milestone rates at 12 months, ratios of OS milestone RMSTs at 12 and 24 months, and HR for OS. The results indicate that OS milestone rates and OS milestone RMSTs could be considered surrogate endpoints of OS in future first-line immunotherapy trials for ES-SCLC.

Download Full-text

Initial management of small-cell lung cancer (limited- and extensive-stage) and the role of thoracic radiotherapy and first-line chemotherapy: a systematic review

Current Oncology ◽

10.3747/co.26.4481 ◽

2019 ◽

Vol 26 (3) ◽

Cited By ~ 5

Author(s):

A. Sun ◽

L. D. Durocher-Allen ◽

P. M. Ellis ◽

Y. C. Ung ◽

J. R. Goffin ◽

...

Keyword(s):

Lung Cancer ◽

Systematic Review ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Platinum Agent ◽

Extensive Stage

Background Patients with limited-stage (ls) or extensive-stage (es) small-cell lung cancer (sclc) are commonly given platinum-based chemotherapy as first-line treatment. Standard chemotherapy for patients with ls sclc includes a platinum agent such as cisplatin combined with the non-platinum agent etoposide. The objective of the present systematic review was to investigate the efficacy of adding radiotherapy to chemotherapy in patients with es sclc and to determine the appropriate timing, dose, and schedule of chemotherapy or radiation for patients with sclc.Methods The medline and embase databases were searched for randomized controlled trials (rcts) comparing treatment with radiotherapy plus chemotherapy against treatment with chemotherapy alone in patients with es sclc. Identified rcts were also included if they compared various timings, doses, and schedules of treatment for patients with es sclc or ls sclc.Results Sixty-four rcts were included. In patients with ls sclc, overall survival was greatest with platinum– etoposide compared with other chemotherapy regimens. In patients with es sclc, overall survival was greatest with chemotherapy containing platinum–irinotecan than with chemotherapy containing platinum–etoposide (hazard ratio: 0.84; 95% confidence interval: 0.74 to 0.95; p = 0.006). The addition of radiation to chemotherapy for patients with es sclc showed mixed results. There was no conclusive evidence that the timing, dose, or schedule of thoracic radiation affected treatment outcomes in sclc.Conclusions In patients with ls sclc, cisplatin–etoposide plus radiotherapy should remain the standard therapy. In patients with es sclc, the evidence is insufficient to recommend the addition of radiotherapy to chemotherapy as standard practice to improve overall survival. However, on a case-by-case basis, radiotherapy might be added to reduce local recurrence. The most commonly used chemotherapy is platinum–etoposide; however, platinum– irinotecan can be considered.

Download Full-text

Multitrial Evaluation of Progression-Free Survival as a Surrogate End Point for Overall Survival in First-Line Extensive-Stage Small-Cell Lung Cancer

Journal of Thoracic Oncology ◽

10.1097/jto.0000000000000548 ◽

2015 ◽

Vol 10 (7) ◽

pp. 1099-1106 ◽

Cited By ~ 17

Author(s):

Nathan R. Foster ◽

Lindsay A. Renfro ◽

Steven E. Schild ◽

Mary W. Redman ◽

Xiaofei F. Wang ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Progression Free Survival ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Free Survival ◽

Extensive Stage

Download Full-text

Associations between TS, TTF-1, FR-α, FPGS, and Overall Survival in Patients with Advanced Non–Small-Cell Lung Cancer Receiving Pemetrexed Plus Carboplatin or Gemcitabine Plus Carboplatin as First-Line Chemotherapy

Journal of Thoracic Oncology ◽

10.1097/jto.0b013e3182a406a3 ◽

2013 ◽

Vol 8 (10) ◽

pp. 1255-1264 ◽

Cited By ~ 24

Author(s):

Bjørn H. Grønberg ◽

Marius Lund-Iversen ◽

Erik H. Strøm ◽

Odd Terje Brustugun ◽

Helge Scott

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Line Chemotherapy

Download Full-text

Front Line Applications and Future Directions of Immunotherapy in Small-Cell Lung Cancer

Cancers ◽

10.3390/cancers13030506 ◽

2021 ◽

Vol 13 (3) ◽

pp. 506

Author(s):

Selina K. Wong ◽

Wade T. Iams

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Checkpoint Inhibitors ◽

Standard Of Care ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Limited Stage ◽

Extensive Stage

After being stagnant for decades, there has finally been a paradigm shift in the treatment of small-cell lung cancer (SCLC) with the emergence and application of immune checkpoint inhibitors (ICIs). Multiple trials of first-line ICI-chemotherapy combinations have demonstrated survival benefit compared to chemotherapy alone in patients with extensive-stage SCLC, establishing this as the new standard of care. ICIs are now being applied in the potentially curative limited-stage setting, actively being investigated as concurrent treatment with chemoradiation and as adjuvant treatment following completion of chemoradiation. This review highlights the evidence behind the practice-changing addition of ICIs in the first-line setting of extensive-stage SCLC, the potentially practice-changing immunotherapy trials that are currently underway in the limited-stage setting, and alternate immunotherapeutic strategies being studied in the treatment of SCLC.

Download Full-text

Partial Response in an RRx-001-Primed Patient with Refractory Small-Cell Lung Cancer after a Third Introduction of Platinum Doublets

Case Reports in Oncology ◽

10.1159/000446209 ◽

2016 ◽

Vol 9 (2) ◽

pp. 285-289 ◽

Cited By ~ 10

Author(s):

Corey A. Carter ◽

Bryan Oronsky ◽

Scott Caroen ◽

Jan Scicinski ◽

Aiste Degesys ◽

...

Keyword(s):

Lung Cancer ◽

Partial Response ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Platinum Drug ◽

First Line Therapy ◽

Extensive Stage

Small-cell lung cancer (SCLC), initially exquisitely sensitive to first-line cisplatin/etoposide, invariably relapses and acquires a multidrug chemoresistant phenotype that generally renders retreatment with first-line therapy both futile and counterproductive. This report presents the case of a 77-year-old Caucasian male with extensive-stage refractory SCLC who was restarted on platinum doublets as part of a clinical trial called TRIPLE THREAT (NCT02489903) involving pretreatment with the epi-immunotherapeutic agent RRx-001, and who achieved a partial response after only 4 cycles. The patient had received a platinum drug twice before, in 2009 for a diagnosis of non-small-cell lung cancer (squamous cell carcinoma) and in 2015 for SCLC, suggesting that RRx-001 pretreatment may sensitize or resensitize refractory SCLC patients to first-line chemotherapy.

Download Full-text

Treatment Patterns and Overall Survival Associated with First-Line Systemic Therapy for Patients with Advanced Non-Small Cell Lung Cancer

Journal of Managed Care & Specialty Pharmacy ◽

10.18553/jmcp.2017.23.2.195 ◽

2017 ◽

Vol 23 (2) ◽

pp. 195-205 ◽

Cited By ~ 4

Author(s):

Michele M. Spence ◽

Rita L. Hui ◽

Jennifer T. Chang ◽

Joanne E. Schottinger ◽

Mirta Millares ◽

...

Keyword(s):

Lung Cancer ◽

Overall Survival ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Systemic Therapy ◽

Treatment Patterns ◽

Small Cell ◽

Small Cell Lung ◽

First Line

Download Full-text

Use of Immunotherapy in Extensive-Stage Small Cell Lung Cancer

Oncology ◽

10.1159/000508516 ◽

2020 ◽

Vol 98 (11) ◽

pp. 749-754 ◽

Cited By ~ 1

Author(s):

Venu Madhav Konala ◽

Bhaskar Reddy Madhira ◽

Sara Ashraf ◽

Stephen Graziano

Keyword(s):

Lung Cancer ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Initial Response ◽

The United States ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Stage Disease ◽

Extensive Stage

Lung cancer is a leading cause of cancer death in the United States and around the world. Approximately 13% of lung cancers are small cell lung cancer (SCLC). SCLC is generally classified as a limited-stage and extensive-stage disease depending on the extent of involvement. For patients with the extensive-stage disease, until recently, chemotherapy alone has been the recommended treatment, although radiotherapy could be used in select patients for palliation of symptoms. The standard of care for extensive-stage SCLC is platinum doublet chemotherapy with either cisplatin or carboplatin in combination with etoposide. Even though first-line therapy has an initial response rate of 60–80%, the prognosis is poor, with overall survival of 10–12 months. The only FDA-approved second line of therapy is topotecan, approved both as an intravenous formulation as well as an oral formulation, with response rates of 6–12% in chemorefractory disease and 15–37% in chemosensitive disease. Immunotherapy has recently been approved as a first-line agent in metastatic SCLC in combination with chemotherapy. It is also approved as a third-line agent in metastatic SCLC after the failure of two chemotherapy regimens. The FDA approved four drugs, two of them being PD-1 inhibitors (pembrolizumab, nivolumab), and two of them being PD-L1 inhibitors (atezolizumab and durvalumab) in SCLC. This review article summarizes the significance of immunotherapy in the treatment of extensive-stage SCLC, its side effects, and limitations.

Download Full-text

Survival and Toxicity After Cisplatin Plus Etoposide Versus Carboplatin Plus Etoposide for Extensive-Stage Small-Cell Lung Cancer in Elderly Patients

Journal of Oncology Practice ◽

10.1200/jop.2016.012492 ◽

2016 ◽

Vol 12 (7) ◽

pp. 666-673 ◽

Cited By ~ 5

Author(s):

Laura A. Hatfield ◽

Haiden A. Huskamp ◽

Elizabeth B. Lamont

Keyword(s):

Lung Cancer ◽

Health Care ◽

Elderly Patients ◽

Small Cell Lung Cancer ◽

Cell Lung Cancer ◽

Odds Ratio ◽

Small Cell ◽

Small Cell Lung ◽

First Line ◽

Extensive Stage

Purpose: Elderly patients with cancer are under-represented in clinical trials and risk greater toxicity from chemotherapy. These patients and their physicians need better evidence to decide among guideline-recommended regimens. We test whether patients with extensive-stage small-cell lung cancer (ES SCLC) have noninferior survival and less hospital-based health care after carboplatin/etoposide compared with cisplatin/etoposide. Methods: We analyzed SEER-Medicare data for beneficiaries with ES SCLC diagnosed at age 67 years and older between 1995 and 2009. Among patients treated with first-line chemotherapy in the ambulatory setting, 831 received cisplatin/etoposide and 2,846 received carboplatin/etoposide. Propensity score matching (2:1 ratio) yielded 778 cisplatin/etoposide and 1,502 carboplatin/etoposide patients. Results: Survival was nearly identical in the two groups: 35.7 weeks for cisplatin/etoposide and 35.9 weeks for carboplatin/etoposide. The hazard ratio of 1 (95% CI, 0.91 to 1.09) excluded our prespecified threshold, indicating noninferiority. Mortality at 6 months was indistinguishable: 35% for cisplatin/etoposide and 34% for carboplatin/etoposide. After carboplatin/etoposide, patients were less likely to be admitted to a hospital (80% v 86%, P < .001) and had fewer hospitalizations (median 1 v 2, odds ratio 0.76, 95% CI, 0.65 to 0.9), ED visits (median 1 v 2, odds ratio 0.82, 95% CI, 0.7 to 0.96), and ICU stays (median 0 v 0, odds ratio 0.82, 95% CI, 0.69 to 0.99). Conclusion: First-line carboplatin/etoposide is associated with similar survival and less subsequent hospital-based health care use than cisplatin/etoposide among elderly patients with ES SCLC treated in ambulatory settings.

Download Full-text