An Italian study showed that chemotherapy was superior to targeted therapy in patients with wild-type metastatic non-small cell lung cancer (NSCLC). The mean progression-free survival for the second-line treatment drug polyenol paclitaxel was significantly better than for erlotinib, at 3.4 months and 2.4 months, respectively (p=0.014). However patients actually taking polyenol paclitaxel were still alive at 6 months. Zhifeng Guo, Department of Medical Oncology, Chifeng Hospital
Marina Garassino, MD, PhD, noted at the American Society of Clinical Oncology meeting that “polyene paclitaxel is more effective for KRAS mutants as well as wild-type tumors.” Garassino, of the Fatebenefratelli & Eye Hospital in Milan, said, “The TAILOR trial is the only prospective, one-to-one trial to compare the efficacy of polyenol paclitaxel with erlotinib in the treatment of patients with wild-type epidermal growth factor receptor (EGFR) overexpression. Polyene paclitaxel significantly improved progression-free survival, remission rates and disease control rates in patients over erlotinib.”
She added, “In second-line therapy, the KRAS gene did not appear to be a prognostic influence.” Erlotinib, a tyrosine kinase inhibitor, has a therapeutic effect on the epidermal growth factor receptor in aggressive non-small cell lung cancer. when the TAILOR trial began in 2007, the drug’s effectiveness in treating EGFR wild-type tumors was not yet proven. This clinical trial was designed to compare the efficacy of polyene paclitaxel with erlotinib as a second-line treatment in treating patients with wild-type EGFR tumors.
In addition, the investigators sought to determine the effect on KRAS gene mutations during treatment with chemotherapy or EGFR inhibitors. After more than three years in the clinical phase, ASCO issued a tentative clinical opinion to test for EGFR mutations before using EGFR inhibitors as first-line therapeutics for non-small cell lung cancer.
The primary clinical indicator was overall survival in patients with wild-type EGFR tumors and the statistically significant result of the trial that polyenol paclitaxel was more effective than erlotinib. Secondary clinical indicators were progression-free survival, remission rates, safety and quality of life.
All patients diagnosed with EGFR wild-type tumors were required to undergo KRAS genetic testing and receive platinum chemotherapy as first-line therapy. And then patients were randomized to treatment with polyene paclitaxel and erlotinib until disease progression or intolerable toxicity. Garassino only announced the results of secondary clinical indicators because there were not enough deaths to calculate the overall survival rate.
The trial analysis included 219 patients with a mean age of 66 years. Three-quarters of these patients were current or past smokers, and 23% had KRAS mutant tumors. The change in PFS in the polyene paclitaxel group was a 31% reduction in the risk of death. There was a 28.9% PFS to 6 months compared to 16.9% in the erlotinib group. PFS was measured using KRAS gene levels: patients with KRAS gene mutations had a mean PFS of 2.6 months and 25.3% reached 6 months, while those without KRAS mutations had a mean PFS of 2.4 months and 21.9% reached 6 months PFS, and none of them were statistically significant.
Multivariate factor analysis demonstrated that only ECOG physical status score (2 vs. 0/1) and allocation therapy predicted PFS each (HR 3.19, P<0.0001 and HR 0.70, P=0.019, respectively). Comparing KRAS gene mutation and wild-type tumors, the risk ratio was 0.87, which was not statistically significant (P=0.441). Subgroup analysis showed consistent results indicating an advantage in the polyene paclitaxel group, both in terms of score, histology, gender, smoking status and KRAS levels. Response data also favored the polyene paclitaxel group with a complete remission rate of 4.3%, a local remission rate of 9.6%, a stable disease rate of 27.6% and an aggressive disease rate of 58.5%. The relative erlotinib group data were 0%, 2.2%, 20.6%, and 77.2%, respectively (P=0.002).
The overall response and clinical benefit rates in the polyene-paclitaxel group were also significantly superior, 13.9% versus 2.2%, P=0.004 and 41.5% versus 22.8%, P=0.007, respectively, compared to the erlotinib group. although the results clearly demonstrate the benefits of polyene-paclitaxel, none of the oncologists in the audience were interested in either drug.
Steven E. Vogl of the Bronx, N.Y. internship asked, “You’re concluding that polyenylated paclitaxel is not a good drug and erlotinib is a worse drug and we should no longer give these drugs to patients who don’t have the mutation, right?”
Until the applause and laughter subsided, Garassino smiled and replied, “I think you’re right.” Invited guest Dr. Benjamin Solomon disagreed with this exchange between Vogl and Garassino. He went on to say, “EGFR wild-type patients have a different body type and we should test for ALK gene recombination and the possibility of other potential mutations.” Solomon, of the Peter MacCallum Cancer Centre in Melbourne, Australia, said, “Although second-line treatment for non-small cell lung cancer does not have good outcomes, we need better treatment, and we need to choose the best from the treatments that are available. This means that chemotherapy is superior to EGFR TKls [tyrosine kinase inhibitors] in the second-line treatment of patients with EGFR wild-type non-small-cell lung cancer. He went on to say, “EGFR wild-type patients have a different body type, and we should test for the possibility of ALK gene recombination as well as other potential gene mutations.”