Cisplatin/Pemetrexed Followed by Maintenance Pemetrexed Versus Carboplatin/Paclitaxel/Bevacizumab Followed by Maintenance Bevacizumab in Advanced Nonsquamous Lung Cancer: The GOIM (Gruppo Oncologico Italia Meridionale) ERACLE Phase III Randomized Trial

doi:10.1016/j.cllc.2014.12.002

Clinical Lung Cancer

Volume 16, Issue 4, July 2015, Pages 262-273

https://doi.org/10.1016/j.cllc.2014.12.002 Get rights and content

Abstract

Introduction

Cisplatin with pemetrexed (CP) and carboplatin with paclitaxel and bevacizumab (CbTB) are standard first-line treatments for patients with advanced nonsquamous (NS) non–small-cell lung cancer (NSCLC). Quality of life (QoL) is a key objective in the management of advanced NSCLC. Thus, effect on QoL could be an additional factor in the choice of treatment.

Patients and Methods

Patients with untreated stage IIIB/IV NS-NSCLC and Eastern Cooperative Oncology Group performance status of 0 or 1 were randomized to receive first-line chemotherapy with cisplatin 75 mg/m² and pemetrexed 500 mg/m², every 3 weeks, for 6 cycles followed by maintenance pemetrexed; or carboplatin area under the curve 6, paclitaxel 200 mg/m², and bevacizumab 15 mg/kg, every 3 weeks, for 6 cycles followed by maintenance bevacizumab. The primary end point was the difference in QoL between the 2 treatment arms after 12 weeks of maintenance, measured using the EuroQoL 5 Dimensions-Index (EQ5D-I) and EQ5D-visual analogue scale (EQ5D-VAS).

Results

One hundred eighteen patients were randomized to CP (n = 60) or CbTB (n = 58). Baseline characteristics were well balanced. The proportion of patients evaluable for the primary end point was lower than planned. After 12 weeks of maintenance, the difference between mean changes in EQ5D-I was 0.137, favoring CP (95% confidence interval [CI], −0.02 to 0.29, Wilcoxon P = .078), although not statistically significant; and the difference between mean changes in EQ5D-VAS was 0.97 (95% CI, −9.37 to 11.31, Wilcoxon P = .41).

Conclusion

Although the study was underpowered because of a small number of patients evaluable for the primary end point, QoL did not differ between treatment arms. Other factors such as comorbidities and schedule should be used when deciding on first-line treatment.

Introduction

Nonsquamous (NS) non–small-cell lung cancer (NSCLC) comprises most lung cancers. Because most patients have metastatic disease at the time of diagnosis, a palliative treatment with platinum-based chemotherapy is considered the standard of care for patients without epidermal growth factor receptor (EGFR) mutations, with the main end point being improvement of survival and quality of life (QoL).¹

Two regimens are widely used for the management of advanced NS-NSCLC: carboplatin, paclitaxel, and bevacizumab (CbTB)² and cisplatin with pemetrexed (CP).³ Therefore, patients treated with both of these common regimens can receive a maintenance phase after the platinum-based induction. Like in the pivotal trial demonstrating its efficacy, bevacizumab is continued until progression in patients treated with CbTB.² In patients without progression after CP, the latter drug can be administered as continuation maintenance until progression, because this strategy has shown to further improve outcomes in advanced NS-NSCLC patients.⁴

Symptom palliation and QoL are key goals in the treatment of patients with advanced NSCLC. EuroQoL 5 Dimensions (EQ5D), consisting of a 5-domain list and a visual analogue scale (VAS), is a standardized health-related QoL questionnaire developed by the EuroQol Group to provide a simple, generic measure of health for clinical and economic appraisal.5, 6, 7 EQ5D is an indirect measure of utility for health that generates an index-based summary score based on societal preference weights.⁸

Although no direct comparisons of CP followed by maintenance pemetrexed versus CbTB followed by maintenance bevacizumab are available, the efficacy of the 2 regimens in patients with advanced NS-NSCLC is expected to be similar. Thus, the effect on QoL of each of the regimens could be a potentially relevant factor in making a treatment choice.

Cisplatin/pEmetRexed followed by mAintenance pemetrexed versus CarbopLatin/paclitaxEl/bevacizumab followed by maintenance bevacizumab in advanced non squamous lung cancer (ERACLE) is a phase III, multicenter, randomized, parallel arm trial comparing CP followed by maintenance pemetrexed versus CbTB followed by maintenance bevacizumab, with the evaluation of QoL according to the EQ5D as the primary end point. The study aim was to detect, if existing, a clinically interesting difference in QoL between the 2 treatment arms.

Section snippets

Study Population

All patients had chemotherapy-naive stage IIIB/IV histologically or cytologically proven NS-NSCLC.⁹ Inclusion required: Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 1; age 18 to 70 years; measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST; version 1.1)¹⁰ that had not been previously irradiated; a life expectancy longer than 12 weeks; adequate bone marrow, renal, and hepatic functions; and coagulation parameters with International

Baseline Characteristics

From January 2011 to March 2012, 118 patients were randomized in 14 Italian centers: 60 patients were assigned to the CP arm and 58 patients were assigned to the CbTB arm (Figure 1). Baseline patient and disease characteristics were similar in the 2 arms (Table 1).

Treatment Compliance

In both study arms, all patients received at least 1 cycle of assigned treatment, and all patients were included in the analysis of ORR, toxicity, and time-to-event outcomes. Overall, 8 patients in the CP arm (13.3%) and 14 patients

Discussion

Cisplatin/pEmetRexed followed by mAintenance pemetrexed versus CarbopLatin/paclitaxEl/bevacizumab followed by maintenance bevacizumab in advanced non squamous lung cancer (ERACLE) is the first randomized trial to compare cisplatin and pemetrexed followed by maintenance pemetrexed versus carboplatin, paclitaxel, and bevacizumab followed by maintenance bevacizumab in NS-NSCLC patients, with QoL as the primary end point. The bevacizumab-based regimen was developed and proven efficacious in the

Conclusion

There was no statistically significant difference in QoL between the 2 regimens, although the change in EQ5D Index was better with CP compared with CbTB, with a difference in mean changes between arms in this coprimary end point that was equal to the MID (0.137). However, ERACLE was not designed or powered to demonstrate equivalence of QoL for the treatment regimens thus, this is a negative results study. The efficacy results are consistent with other phase III first-line studies of platinum

Disclosure

Domenico Galetta, Massimo Di Maio and Giuseppe Colucci received honoraria for advisory board by Eli Lilly Italia. Saverio Cinieri, Vittorio Gebbia and Alessandro Morabito received honoraria for advisory board by Eli Lilly and Roche. The remaining authors have stated that they have no conflicts of interest.

Acknowledgments

Cisplatin/pEmetRexed followed by mAintenance pemetrexed versus CarbopLatin/paclitaxEl/bevacizumab followed by maintenance bevacizumab in advanced non squamous lung cancer (ERACLE) was a nonprofit, academic trial promoted by Gruppo Oncologico Italia Meridionale. Eli Lilly supported the trial and supplied pemetrexed administered as maintenance treatment (all other drugs were registered and reimbursed for use in clinical practice).

References (20)

P. Goldstraw et al.
International Association for the Study of Lung Cancer International Staging Committee; Participating Institutions. The IASLC Lung Cancer Staging Project: proposals for revision of the stage groupings in the forthcoming (seventh) edition of the TNM
J Thorac Oncol
(2007)
E.A. Eisenhauer et al.
New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1)
Eur J Cancer
(2009)
M. Schemper et al.
A note on quantifying follow-up in studies of failure time
Control Clin Trials
(1996)
G. D'Addario et al.
Metastatic non–small-cell lung cancer: ESMO clinical practice guidelines for diagnosis, treatment and follow-up
Ann Oncol
(2010)
A. Rossi et al.
Six versus fewer planned cycles of first-line platinum-based chemotherapy for non–small-cell lung cancer: a systematic review and meta-analysis of individual patient data
Lancet Oncol
(2014)
A. Sandler et al.
Treatment outcomes by tumor histology in Eastern Cooperative Group study E4599 of bevacizumab with paclitaxel/carboplatin for advanced non–small-cell lung cancer
J Thorac Oncol
(2010)
R. Govindan et al.
Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the Surveillance, Epidemiologic, and End Results database
J Clin Oncol
(2006)
A. Sandler et al.
Paclitaxel-carboplatin alone or with bevacizumab for non–small-cell lung cancer
N Engl J Med
(2006)
G.V. Scagliotti et al.
Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer
J Clin Oncol
(2008)
L.G. Paz-Ares et al.
PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer
J Clin Oncol
(2013)

There are more references available in the full text version of this article.

Cited by (52)

Long-term comparative efficacy and safety of nivolumab plus ipilimumab relative to other first-line therapies for advanced non-small-cell lung cancer: A systematic literature review and network meta-analysis
2023, Lung Cancer
To quantify the long-term comparative efficacy and safety of nivolumab in combination with ipilimumab (NIVO + IPI) relative to other immunotherapy (IO)-based regimens and chemotherapy in patients with first-line advanced non-small cell lung cancer (aNSCLC).
Phase 3 randomized controlled-trials (RCTs) with minimum 3-year follow-up evaluating IO-based regimens approved for first-line aNSCLC were identified via systematic literature review. Analytic populations were defined by levels of PD-L1 expression and histology. Due to presence of proportional hazards violations, time-varying hazard ratios (HRs) of overall survival (OS) and progression-free survival (PFS) were estimated via Bayesian fractional polynomial network meta-analysis. For safety endpoints, odds ratios (ORs) were estimated using indirect treatment comparisons (ITCs).
CheckMate 227, KEYNOTE-189, KEYNOTE-407, KEYNOTE-024, KEYNOTE-042, and IMpower150 were included in the base case analysis. For OS and PFS, HRs of NIVO + IPI relative to other IO-based regimens trended downward over time across analytic populations. The 36-month OS HRs of NIVO + IPI versus comparators were: 0.69 (95 % credible interval: 0.47, 1.00) versus pembrolizumab + chemotherapy and 0.65 (0.45, 0.93) versus atezolizumab + bevacizumab + chemotherapy in the non-squamous and PD-L1 all-comers population; 0.73 (0.53, 1.02) versus pembrolizumab + chemotherapy in the squamous and PD-L1 all-comers population; and 1.05 (0.83, 1.32) versus pembrolizumab in the mixed histology and PD-L1 ≥ 50 % population. For PFS, 36-month HR point estimates ranged from 0.46 to 0.85 (only statistically significant versus pembrolizumab + chemotherapy in the squamous population; 0.46 [0.31, 0.69]). Adverse events (AEs) leading to discontinuation were not statistically significantly different between NIVO + IPI and pembrolizumab + chemotherapy, nor between NIVO + IPI and pembrolizumab monotherapy, although treatment-related grade ≥ 3 AEs were higher with NIVO + IPI than pembrolizumab monotherapy (OR = 2.21 [1.30, 3.75]).
This study indicates trends towards long-term benefit with NIVO + IPI compared with other IO-based combinations, with manageable toxicities.
Correlations between objective response rate and survival-based endpoints in first-line advanced non-small cell lung Cancer: A systematic review and meta-analysis
2022, Lung Cancer
The study objective was to estimate the relationship between objective response and survival-based endpoints by drug class, in first-line advanced non-small cell lung cancer (aNSCLC).
A systematic literature review identified randomized controlled trials (RCTs) of first-line aNSCLC therapies reporting overall survival (OS), progression-free survival (PFS), and/or objective response rate (ORR). Trial-level and arm-level linear regression models were fit, accounting for inclusion of immunotherapy (IO)-based or chemotherapy-only RCT arms. Weighted least squares-based R² were calculated along with 95% confidence intervals (CIs). For the main trial-level analysis of OS vs. ORR, the surrogate threshold effect was estimated. Exploratory analyses involved further stratification by: IO monotherapy vs. chemotherapy, dual-IO therapy vs. chemotherapy, and IO + chemotherapy vs. chemotherapy.
From 17,040 records, 57 RCTs were included. In the main analysis, trial-level associations between OS and ORR were statistically significant in both the IO-based and chemotherapy-only strata, with R² estimates of 0.54 (95% CI: 0.26–0.81) and 0.34 (0.05–0.63), respectively. OS gains associated with a given ORR benefit were statistically significantly larger within IO vs. chemotherapy comparisons compared to chemotherapy vs. chemotherapy comparisons (p < 0.001). Exploratory analysis suggested a trend by IO type: for a given change in ORR, ‘pure’ IO (IO monotherapy and dual-IO) vs. chemotherapy RCTs tended to have a larger OS benefit than IO + chemotherapy vs. chemotherapy RCTs. For ORR vs. PFS, trial-level correlations were strong in the IO-based vs. chemotherapy (R² = 0.84; 0.72–0.95), and chemotherapy vs. chemotherapy strata (R² = 0.69; 0.49–0.88). For OS vs. PFS, correlations were moderate in both strata (R² = 0.49; 0.20–0.78 and R² = 0.49; 0.23–0.76).
The larger OS benefit per unit of ORR benefit in IO-based RCTs compared to chemotherapy-only RCTs provides an important addition to the established knowledge regarding the durability and depth of response in IO-based treatments.
Overall Survival and Safety With Pemetrexed/Platinum ± Anti-VEGF Followed by Pemetrexed ± Anti-VEGF Maintenance in Advanced Nonsquamous Non–Small-Cell Lung Cancer: A Pooled Analysis of 4 Randomized Studies
2022, Clinical Lung Cancer
Citation Excerpt :
Consistent with previous literature, there was no superior OS benefit between patients receiving pemetrexed-only maintenance and pemetrexed + anti-VEGF therapy. The median OS rates reported here for patients receiving pemetrexed-only maintenance (16.1 months) were similar to previous pemetrexed maintenance therapy trials, (PARAMOUNT: 16.9 months; PRONOUNCE: 10.5 months; ERACLE: 14.0 months; and ECOG-ACRIN 5508: 15.9 months).4,6,17,19,23 Median OS for patients receiving pemetrexed + anti-VEGF maintenance (18.4 months) was also similar to other trials investigating pemetrexed + bevacizumab maintenance, including the AVAPERL trial (17.1 months)14,15 and the ECOG-ACRIN 5508 trial (16.4 months).17
Before immune checkpoint blockade therapy, chemotherapy with pemetrexed maintenance was the standard of care for patients with advanced nonsquamous non–small-cell lung cancer (NSQ-NSCLC) and remains such where immunotherapy is not applicable. This pooled analysis aimed to characterize overall survival (OS) and safety of pemetrexed ± anti-VEGF maintenance, by treatment duration.
Data from 4 randomized clinical trials (PARAMOUNT, PRONOUNCE, PointBreak, JVBL) of patients with NSQ-NSCLC receiving pemetrexed ± anti-VEGF maintenance therapy were pooled as 2 groups (Group A: pemetrexed-only maintenance, n = 486; and Group B: pemetrexed + anti-VEGF maintenance, n = 329). OS and treatment-emergent adverse events (TEAEs) were analyzed in both groups by treatment duration.
Baseline characteristics were well balanced between both groups. Median OS did not significantly differ between Group A (16.1 months) and Group B (18.4 months; hazard ratio: 1.17, P= .1417). A correlation between median OS and treatment duration was numerically stronger in Group A (r = 0.72) versus B (r = 0.62). Across treatment groups, TEAEs were largely grade 1 to 2 and, with few exceptions, did not increase with increased treatment duration.
There was no significant OS difference between pemetrexed-only and pemetrexed ± anti-VEGF maintenance in patients with NSQ-NSCLC. Patients receiving pemetrexed + anti-VEGF experienced a slightly less favorable safety profile with more reported TEAEs compared to pemetrexed monotherapy. Pemetrexed ± anti-VEGF maintenance therapy may be considered in NSQ-NSCLC, based on an individualized patient approach, particularly where immunotherapy is not clinically indicated.
Antiangiogenic drugs: Chemosensitizers for combination cancer therapy
2022, Antiangiogenic Drugs as Chemosensitizers in Cancer Therapy: volume 18
Angiogenesis is a key step in tumor progression and recurrence, and is known as a hallmark of solid tumors. The architecture of the tumor vasculature is deregulated, vessels are immature, and their functionality is defective, causing increase of interstitial pressure, hypoxia, and acidity in the tumor microenvironment, and favoring an enhanced tumor dissemination and metastasis. The defective tumor vasculature as well as the modifications of tumor microenvironment are a barrier for the effective delivery and accumulation of either the anticancer drugs, including antiangiogenic drugs, or immune-competent T cells in tumor area, thus promoting tumor resistance to therapy. Among the various approaches for targeting tumor angiogenesis, vascular normalization and vessel maturation are considered the most promising approaches, which favor both an effective delivery of anticancer drugs and accumulation of immune-competent T cells into the tumor area. Antiangiogenic therapy can downregulate continuous angiogenic signaling and result in vascular normalization, such as pruning, vascular maturation, and increased perfusion. Thus, antiangiogenic drugs are now considered promising chemosensitizers of anticancer strategies such as chemotherapy, target therapies, and immune checkpoint inhibitors in several advanced tumors. This review summarizes the current understanding and clinical development of combination therapy with antiangiogenic drugs and anticancer chemo-, targeted, and immune therapies.
Superior Effectiveness of PD-1 Inhibitor Plus Chemotherapy versus Bevacizumab Plus Chemotherapy as First-Line Treatment for Non-Small Cell Lung Cancer with Brain Metastases
2024, Advanced Therapeutics
Research progress and potential medical applications of anaplastic lymphoma kinase in treatment of non-small cell lung cancer
2024, Chinese Pharmacological Bulletin

View all citing articles on Scopus

: EudraCT study number 2009-015807-19 and ClinicalTrials.gov Identifier NCT01303926

: Current address for Massimo Di Maio: Department of Oncology, University of Turin, Orbassano, Turin, Italy

View full text

Original StudyCisplatin/Pemetrexed Followed by Maintenance Pemetrexed Versus Carboplatin/Paclitaxel/Bevacizumab Followed by Maintenance Bevacizumab in Advanced Nonsquamous Lung Cancer: The GOIM (Gruppo Oncologico Italia Meridionale) ERACLE Phase III Randomized Trial

Abstract

Introduction

Patients and Methods

Results

Conclusion

Introduction

Section snippets

Study Population

Baseline Characteristics

Treatment Compliance

Discussion

Conclusion

Disclosure

Acknowledgments

J Thorac Oncol

Eur J Cancer

Control Clin Trials

Ann Oncol

Lancet Oncol

J Thorac Oncol

Changing epidemiology of small-cell lung cancer in the United States over the last 30 years: analysis of the Surveillance, Epidemiologic, and End Results database

J Clin Oncol

Paclitaxel-carboplatin alone or with bevacizumab for non–small-cell lung cancer

N Engl J Med

Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non–small-cell lung cancer

J Clin Oncol

PARAMOUNT: final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer

J Clin Oncol

Original Study
Cisplatin/Pemetrexed Followed by Maintenance Pemetrexed Versus Carboplatin/Paclitaxel/Bevacizumab Followed by Maintenance Bevacizumab in Advanced Nonsquamous Lung Cancer: The GOIM (Gruppo Oncologico Italia Meridionale) ERACLE Phase III Randomized Trial