April 25, 2008 — Adding the oral multikinase inhibitor sorafenib (Nexavar, Bayer) to a combination of carboplatin and paclitaxel has shown no benefit in patients with non–small-cell lung cancer (NSCLC) in a large phase 3 trial. In fact, in a small subset of patients with squamous-cell histology, the addition of sorafenib appeared to have a detrimental effect, leading to an increased risk for mortality. As a result, the trial was stopped prematurely.
"We are raising a warning flag to the scientific community," lead investigator Giorgio Scagliotti, MD, PhD, from the University of Torino, in Italy, told Medscape Oncology. "This is an early release of data," he emphasized, but "based on a planned interim analysis, the study showed a clear inferiority after adding sorafenib to carboplatin/paclitaxel in first-line NSCLC patients with squamous history."
Dr. Scagliotti reported the finding today at the 1st European Lung Cancer Conference, being held in Geneva, Switzerland. The meeting was organized jointly by the International Association for the Study of Lung Cancer and the European Society for Medical Oncology.
The study, known as Evaluation of Sorafenib, Carboplatin and Paclitaxel Efficacy in NSCLC (ESCAPE), involved 926 patients. Median overall survival was similar in the 2 treatment groups (10.7 months with carboplatin/paclitaxel/sorafenib and 10.6 months with carboplatin/paclitaxel).
However, in the subset of patients with squamous-cell history (n = 219; 24%) there was significantly greater mortality in the sorafenib group. Patients taking all 3 drugs had a median overall survival of 8.9 months, compared with 13.6 months for patients taking just the 2 drugs.
In the remainder of the patients with non–squamous-cell carcinoma, the median overall survival was 11.5 months in patients treated with the 3 drugs and 10.3 months in those treated with the 2 drugs.
"There was a small number of squamous-cell patients, so we cannot say that there was definitely a detrimental effect, but it looks quite likely," Dr. Scagliotti commented. "But the other side of the story is that in the non–squamous-cell patients there was no evidence of any detrimental effect."
"The medical community should acknowledge that this is an important scientific communication, because we are preventing further harm to patients," Dr. Scagliotti commented in an interview. Also, this could be a class effect, he speculated. Another trial with a similar type of drug (AZ2171), also given in combination with carboplatin and a taxane, has "more or less been stopped in terms of clinical development," he said, after a trial conducted in Canada showed an excess of toxicity.
Isolated Observation From Subset Analysis
"This observation is isolated to this 1 trial," Susan Kelly, MD, vice president of oncology clinical development at Bayer, told Medscape Oncology. "The overall finding was that there was no benefit from having additional sorafenib," she said, "while in the small subset of squamous-cell patients, not only was there no benefit to be derived, the outcome was worse." However, she pointed out that the subset of patients was small and the trial was not designed for this subset to be analyzed; hence, there is no statistical power. "This is an observation from a subset analysis," she emphasized, but agreed that it was an important observation that needs to be discussed within the lung cancer community.
Nothing like this has been seen before with sorafenib, either in combination or in single-agent studies. Dr. Kelly noted. In fact, sorafenib monotherapy has shown a clear survival advantage in liver cancer. This finding of increased mortality stands out because it has shown improved progression-free survival and a trend toward a survival advantage in renal cell carcinoma (both licensed indications for the drug). "We have not been able to find any explanation for this finding," Dr. Kelly said. In particular, there was no increase in adverse bleeding events, she noted, which had been the case in a previous study in which bevacizumab (Avastin, Genentech) was added to chemotherapy in the same patient population.
Another trial with sorafenib in lung cancer is ongoing, Dr. Kelly noted. This trial, known as NEXUS, is studying the addition of sorafenib to a combination of cisplatin and gemcitabine in NSCLC. When the ESCAPE trial was halted, Bayer approached the data-monitoring committee of the NEXUS study and asked to see the results obtained so far, particularly for the subset of patients with squamous-cell carcinoma. Although there was no signal in this subset of patients, the committee recommended that squamous-cell patients taking part in the NEXUS study withdraw and that no further squamous-cell patients be recruited. The study was formally amended and is now is continuing in non–squamous-cell NSCLC.
"I was surprised to hear these new data and cannot offer any explanation," Ulrich Gatzemeier, MD, chief of thoracic oncology at Grosshansdorf Hospital, near Hamburg, Germany, commented to Medscape Oncology. He said that there was a slight increase in complications and adverse effects with the group of patients taking sorafenib, but not enough to explain the increase in mortality. In particular, the rate of bleeding complications was around 1% to 2%, whereas in previous trials the rate reported with bevacizumab was around 4%.
Dr. Gatzemeier said that he had been involved in phase 2 clinical trials with sorafenib used as second-line therapy for NSCLC; the results of those studies showed "clear signs of activity" and an increase in long-term survival. "So I was very surprised to hear that this phase 3 trial was negative," he said.
1st European Lung Cancer Conference: Late-Breaking Abstract. Presented April 25, 2008.
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Cite this: Zosia Chustecka. Addition of Sorafenib May Be Detrimental in Some Lung Cancer Patients - Medscape - Apr 25, 2008.