Lung cancer remains the most frequent cancer in the world. For the moment we don’t have an optimal treatment especially for advanced stages. For that reason there are many studies which try to test new agents or combinations to improve the outcome of this serious disease. Many journals of oncology published a lot of this kind of studies. I present in this paper the studies that I considered to be the most important.
- Efficacy and safety of pemetrexed/cisplatin versus gemcitabine/cisplatin as first-line treatment in Chinese patients with advanced nonsquamous non-small cell lung cancer.
This “retrospective subgroup analysis in JMDB study indicates that the between-arm differences in overall survival (OS) in the East Asian subgroup were consistent with those observed in the entire JMDB study population. This bridging study (JMIL) further evaluated the efficacy and safety of first-line pemetrexed/cisplatin (PC) versus gemcitabine/cisplatin (GC) in Chinese patients with nonsquamous non-small cell lung cancer (NSCLC).
The primary endpoint of this local registration trial was designed to compare OS in the combined dataset, consisting of Chinese patients in JMIL and 1252 nonsquamous patients in JMDB”.
“Chinese patients with stage IIIB/IV nonsquamous NSCLC were randomly assigned (1:1) to 6 cycles maximum (21 days/cycle) of pemetrexed 500 mg/m2+cisplatin 75 mg/m2 (day 1), or gemcitabine 1250 mg/m2 (days 1 and 8)+cisplatin 75 mg/m2 (day 1)”.
This study showed that in the in the Chinese-only population, no significant difference was observed between the patients treated with PC versus patients treated with GC; a better safety and risk/benefit profile was found in the PC arm.
A PC regimen should be considered as a standard of care in Chinese nonsquamous NSCLC patients in a first-line setting.
- Randomized open-label non-comparative multicenter phase II trial of sequential erlotinib and docetaxel versus docetaxel alone in patients with non-small-cell lung cancer after failure of first-line chemotherapy: GFPC 10.02 study.
Auliac JB, Chouaid C, Greiller L, Monnet I, Le Caer H, Falchero L, Corre R, Descourt R, Bota S, Berard H, Schott R, Bizieux A, Fournel P, Labrunie A, Marin B, Vergnenegre A, the GFPC team. Lung Cancer. 2014 Jul 17
This study started from the fact that concomitant administration of erlotinib with standard chemotherapy does not appear to improve survival among patients with non-small-cell lung cancer (NSCLC), but preliminary studies suggest that sequential administration might be effective.
This study (an open label study 0) try to assess the efficacy and tolerability of second-line sequential administration of erlotinib and docetaxel in advanced NSCLC.
Patients with advanced NSCLC, EGFR wild type or unknown, PS 0-2, in whom initial cisplatin-based chemotherapy had failed were randomized to sequential erlotinib 150mg/d (day 2-16)+docetaxel (75mg/m(2) d1) (arm ED) or docetaxel (75mg/m(2) d1) alone (arm D) (21-day cycle).
The primary endpoint was the progression-free survival rate at 15 weeks (PFS 15).
Secondary endpoints included PFS, overall survival (OS), the overall response rate (ORR) and tolerability. Based on a Simon optimal two-stage design, the ED strategy was rejected if the primary endpoint was below 33/66 patients at the end of the two Simon stages.
This study failed to demonstrate that sequential erlotinib and docetaxel was not more effective than docetaxel alone as second-line treatment for advanced NSCLC with wild type or unknown EGFR status.
- Efficacy and safety of maintenance pemetrexed in patients with advanced nonsquamous non-small cell lung cancer following pemetrexed plus cisplatin induction treatment: A cross-trial comparison of two phase III trials.
Two phase III trials of advanced NSCLC patients were compared to examine relative efficacy and safety of different treatment regimens. The JMDB trial investigated first-line pemetrexed-cisplatin.
The PARAMOUNT phase III trial compared maintenance pemetrexed versus placebo after patients with nonsquamous NSCLC completed 4 cycles of first-line pemetrexed-cisplatin without disease progression.
“Overall survival (OS) and progression-free survival (PFS), analyzed by Kaplan-Meier and Cox methods, and toxicity rates were compared between the PARAMOUNT arms and a selected homogeneous population from JMDB.
The across-trial comparison supported the efficacy of the pemetrexed continuation maintenance strategy and suggested the results are not influenced by limiting the pemetrexed-cisplatin induction treatment to four cycles.
Although longer exposure to pemetrexed-cisplatin or maintenance pemetrexed increased some toxicities, the overall incidence remained low, underscoring the relative safety of these treatment regimens”.
- A phase II trial of the Src-kinase inhibitor saracatinib after four cycles of chemotherapy for patients with extensive stage small cell lung cancer: NCCTG trial N-0621.
This study assess the efficacy and the Src-kinase inhibitor saracatinib (AZD-0530) after four cycles of platinum-based chemotherapy for extensive stage small cell lung cancer (SCLC).
Patients with at least stable disease received saracatinib at a dose of 175 mg/day by mouth until disease progression, unacceptable toxicity, or patient refusal. The primary endpoint was the 12-week progression-free survival (PFS) rate from initiation of saracatinib treatment.
All 23 evaluable patients received platinum based standard chemotherapy.
Authors concluded that Saracatinib at a dose of 175 mg/day by mouth is well tolerated.
However, the PFS rate observed at the pre-planned interim analysis did not meet the criteria for additional enrollment.
- Afatinib in the treatment of EGFR mutation-positive NSCLC - A network meta-analysis.
Objectives: Epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC) respond to treatment with tyrosine kinase inhibitors (TKIs).
Two reversible EGFR TKIs (gefitinib, erlotinib) and the irreversible ErbB family blocker afatinib are currently approved for treatment of EGFR mutation-positive NSCLC, but no head-to-head trials have been reported to date.
A network meta-analysis (NMA) was performed to try to compare the efficacy of this drugs.
A systematic literature review was conducted to compare progression-free survival (PFS) and overall survival in trials with mentioned drugs.
Results were analyzed using Bayesian methods.
There were identified 246 articles that were assessed for eligibility, of which 21 studies were included in the NMA, including eight trials performed in an EGFR mutation-positive population.
In the absence of direct head-to-head trial data comparing efficacy between the three EGFR TKIs, authors concluded that afatinib is a viable treatment alternative to erlotinib or gefitinib in terms of PFS.
A direct trial-based comparison of the efficacy of these agents is warranted to clarify their relative benefits.
- EGFR biomarkers predict benefit from vandetanib in combination with docetaxel in a randomized phase III study of second line treatment for patients with advanced non-small cell lung cancer.
The ZODIAC study (a randomized phase III study) assesses second line treatment in patients with advanced non-small cell lung cancer that evaluated the addition of vandetanib to docetaxel.
The study showed a statistically significant improvement in progression-free survival and objective response rate, but not in overall survival for unselected patients (“This study evaluated EGFR gene mutation, copy number gain, and protein expression, and KRAS gene mutation, in pre-treatment tumor samples as potential biomarkers predicting benefit from vandetanib as second-line treatment of non-small-cell lung cancer”).
The conclusion of this study was that high EGFR gene copy number or activating EGFR mutations may identify patient subgroups who receive increased clinical benefit from vandetanib in combination with docetaxel in second-line NSCLC.
CLINICAL TRIAL SGOV: NCT00312377.
- Chemotherapy With or Without Maintenance Sunitinib for Untreated Extensive-Stage Small-Cell Lung Cancer: A Randomized, Double-Blind, Placebo-Controlled Phase II Study-CALGB 30504 (Alliance).
Purpose: To evaluate the efficacy of maintenance sunitinib after chemotherapy for small-cell lung cancer (SCLC).
This study was conducted by the “Cancer and Leukemia Group” B 30504 trial.
It was a randomized, placebo-controlled, phase II study that enrolled patients before chemotherapy (cisplatin 80 mg/m2 or carboplatin area under the curve of 5 on day 1 plus etoposide 100 mg/m2 per day on days 1 to 3 every 21 days for four to six cycles).
Patients without progression were randomly assigned 1:1 to placebo or sunitinib 37.5 mg per day until progression.
Cross-over after progression was allowed. The primary end point was progression-free survival (PFS) from random assignment for maintenance placebo versus sunitinib using a one-sided log-rank test with a = .15; 80 randomly assigned patients provided 89% power to detect a hazard ratio (HR) of 1.67.
This trial was positive and showed that maintenance sunitinib was safe and improved PFS in extensive-stage SCLC.
- A randomized phase 2 study of the MEK1/MEK2 inhibitor trametinib (GSK1120212) compared with docetaxel in KRAS-mutant advanced non-small cell lung cancer (NSCLC).
Blumenschein G, Smit EF, Planchard D, Kim DW, Cadranel J, De Pas T, Dunphy F, Udud K, Ahn MJ,Hanna NH, Kim JH, Mazieres J, Kim SW, Baas P, Rappold E, Redhu S, Puski A, Wu FS, Jänne PA. Ann Oncol. 2015 Feb 26
KRAS mutations are detected in 25% of non-small cell lung cancer (NSCLC) and no targeted therapies are approved for this subset population. Trametinib, a selective allosteric inhibitor of MEK1/MEK2, demonstrated preclinical and clinical activity in KRAS-mutant NSCLC. This phase II trial compare trametinib with docetaxel in patients with advanced KRAS-mutant NSCLC in second line for patients prior treated with platinum based chemotherapy.
Conclusion was: Trametinib showed similar PFS and response rate as docetaxel in the group of patients selected for this study.
- A Meta-Analysis of Resected Metachronous Second Non-Small Cell Lung Cancer.
“This meta-analysis was designed to determine the effect of surgical treatment on overall survival of patients treated surgically for a second non-small cell lung cancer (NSCLC) that occurred after resection of an initial NSCLC.
PubMed and Scopus databases were queried. Nine studies were identified”.
This meta-analyses suggest that surgical resection can be an option for patients who have a second primary NSCLC after resection of an initial lung cancer.
- Adjuvant chemotherapy for resected early-stage non-small cell lung cancer.
Burdett S, Pignon JP, Tierney J, Tribodet H, Stewart L, Le Pechoux C, Aupérin A, Le Chevalier T, Stephens RJ, Arriagada R, Higgins JP, Johnson DH, Van Meerbeeck J, Parmar MK, Souhami RL, Bergman B, Douillard JY, Dunant A, Endo C, Girling D, Kato H, Keller SM, Kimura H, Knuuttila A, Kodama K, Komaki R, Kris MG, Lad T, Mineo T, Piantadosi S, Rosell R, Scagliotti G, Seymour LK, Shepherd FA, Sylvester R, Tada H, Tanaka F, Torri V, Waller D, Liang Y, for the Non‐Small Cell Lung Cancer Collaborative Group. Cochrane Database Syst Rev. 2015 Mar 2; 3:CD011430
The authors performed two systematic reviews and meta-analyses of all randomised controlled trials using individual participant data.
Results were first published in “The Lancet” in 2010. The authors tried to find if a benefit exist for patients who received adjuvant chemotherapy after surgery or after surgery and radiotherapy.
By specific methods authors identified 35 trials evaluating surgery plus adjuvant chemotherapy versus surgery alone.
There was a clear evidence of a benefit of adding chemotherapy after surgery with an absolute increase in survival of 4% at five years.
In other 12 trials evaluating surgery plus radiotherapy plus chemotherapy versus surgery plus radiotherapy alone, authors find out also evidence of a benefit of adding chemotherapy to surgery plus.
Authors concluded that a clear benefit of adjuvant chemotherapy existed for these patients, irrespective of whether chemotherapy was given in addition to surgery or surgery plus radiotherapy.