American Society for Radiation Oncology | Sep 24, 2017
“Long-term results of a phase III clinical trial indicate that survival rates for patients receiving chemoradiation for unresectable, locally advanced non-small cell lung cancer (NSCLC) may be more than twice as high as previous estimates. At five years following treatment with a standard dose of 60 Gray (Gy) radiation delivered in 30 fractions, the overall survival rate was 32 percent, setting a new benchmark of survival for patients with inoperable stage III NSCLC. The trial, RTOG 0617, also confirms that a standard dose of radiation therapy is preferable to a higher dose and that cetuximab offers no additional survival benefit for these patients. Findings will be presented today at the 59th Annual Meeting of the American Society for Radiation Oncology (ASTRO) in San Diego.”
Mutations in the gene that encodes the KRAS protein are frequently encountered in various human cancers. They are found in about 30% of non-small cell lung cancers (NSCLCs), making KRAS the single most common gene mutated in this cancer. The rate of KRAS mutations in other cancers, such as pancreatic or colorectal, is even higher.
A mutant KRAS protein that is always in the “on” position activates many signaling pathways, many of which lead to unrestrained growth and proliferation of cancer cells. This makes KRAS an appealing treatment target. However, challenges abound, and researchers are exploring several different approaches to treating KRAS-mutant cancers.
Unlike mutations in proteins known as receptor tyrosine kinases, like EGFR or ALK, mutated KRAS is a very difficult protein to target with cancer drugs. (So much so that the National Institutes of Health (NIH) has undertaken a special effort to intensify the effort towards successful targeting of mutant KRAS, known as the RAS Initiative.) Continue reading…
“Adding the EGFR inhibitor cetuximab (Erbitux) to chemotherapy failed to improve survival in patients with advanced non-small cell lung cancer, a multicenter randomized trial showed.
“The primary analysis showed a median overall survival of 10.9 months compared with 9.4 months, a difference that did not achieve statistical significance (HR 0.94, 95% CI 0.84-1.06). The trial also failed to demonstrate improvement in progression-free survival for patients with EGFR-positive disease, the co-primary endpoint.
“However, cetuximab led to a 25% reduction in hazard ratio among patients who had EGFR-positive tumors by fluorescence in situ hybridization (FISH) and were not candidates for bevacizumab (Avastin), a prespecified secondary endpoint. An exploratory analysis analysis showed that patients with EGFR-positive, squamous-cell tumors lived almost twice as long with cetuximab as with chemotherapy alone (11.8 vs 6.4 months, P=0.006), as reported here at the World Conference on Lung Cancer.”
The gist: An attempt to improve treatment for stage III non-small cell lung cancer (NSCLC) patients failed when it was tested in a clinical trial. People with stage III NSCLC are normally treated with radiation and chemotherapy. Researchers wondered if giving higher-dose radiation or adding the drug cetuximab (Erbitux) would improve the standard treatment. However, when tested in patients, neither approach worked better than the standard approach.
“As reported in The Lancet Oncology by Bradley and colleagues, the phase III Radiation Therapy Oncology Group 0617 trial showed no survival benefit of high- vs standard-dose radiotherapy or for addition of cetuximab (Erbitux) to concurrent paclitaxel-carboplatin chemoradiation in patients with inoperable stage IIIA or IIIB non–small cell lung cancer (NSCLC).
“In the open-label 2×2 factorial trial, patients from the United States and Canada were randomly assigned 1:1:1:1 between November 2007 and November 2011 to receive 60 Gy radiotherapy (n = 166), 74 Gy radiotherapy (n = 121), 60 Gy radiotherapy and cetuximab (n = 147), or 74 Gy radiotherapy and cetuximab (n = 110) with all patients receiving concurrent once-weekly chemotherapy with paclitaxel at 45 mg/m2 and carboplatin at area under the curve (AUC) 2. Two weeks after chemoradiation, patients received two cycles of consolidation paclitaxel at 200 mg/m2 and carboplatin at AUC 6 separated by 3 weeks. Radiation was given in 2-Gy daily fractions with either intensity-modulated or three-dimensional conformal radiation therapy. Cetuximab was given at 400 mg/m2 on day 1 followed by 250 mg/m2 weekly continued through consolidation therapy. The primary endpoint was overall survival.
“Patients had a median age of 64 years, and most were male (55%–64%), white (82%–89%), had Zubrod performance status of 0 (55%–59%), were current smokers (43%–51%), received three-dimensional conformal radiotherapy (47%–54%), underwent positron-emission tomography (PET) staging (89%–91%), had squamous histology (42%–47%), and had stage IIIA disease (63%–66%).”
Editor’s note: This article discusses the results of a clinical trial—a research study with volunteer patients. The goal of the trial was to compare two drugs—bevacizumab and cetuximab—when they were added to the standard chemotherapy combo FOLFIRI. All patients who participated in the trial had metastatic colorectal cancer. The researchers found that patients treated with FOLFIRI plus cetuximab had longer overall survival times that patients treated with FOLFIRI plus bevacizumab. The results differ from those from another recent study, which found no significant difference between the two treatments.
“Adding cetuximab (Erbitux) to the standard first-line FOLFIRI chemotherapy regimen resulted in longer overall survival compared with FOLFIRI plus bevacizumab (Avastin) in patients with metastatic colorectal cancer, according to results of the phase III FIRE-3 trial published this month in the Lancet.
“This result was seen in patients with a wild-type exon 2 KRAS gene. The longer overall survival was observed despite there being no significant difference in objective response between the two study groups.
“The study analyzed data from 592 patients with KRAS exon 2 wild-type colorectal cancer treated with FOLFORI and either cetuximab (an epidermal growth factor receptor inhibitor) or bevacizumab (an angiogenesis inhibitor). Patients were recruited at 116 Austrian and German cancer centers.”
Editor’s note: This article describes the results of a clinical trial—a research study with volunteer patients. The goal of the trial was to compare four different treatments for metastatic colorectal cancer (mCRC). All patients took a combination of chemotherapy drugs; either FOLFIRI [which combines folinic acid, fluorouracil and irinotecan] or FOLFOX [folinic acid, 5-fluorouracil and oxaliplatin]. Patients also took a targeted drug alongside the chemo; either bevacizumab (aka Avastin) or cetuximab (Erbitux). All four treatment combinations resulted in similar survival times—a median of 29 months. Compared to other clinical trials, this is a relatively long survival time. Based on these results, oncologists will now have more options for treating their patients according to patients’ preferences and side effects.
“Patients with KRAS wild-type metastatic colorectal cancer (mCRC) receiving first-line treatment with a chemotherapy backbone plus bevacizumab or cetuximab survived for a median of 29 months, the longest median survival time reported in a major trial of these severely ill patients.
“Importantly, survival times were the same, whether patients received the anti–vascular endothelial growth factor bevacizumab (Avastin, Genentech) or the anti–epidermal growth factor receptor (EGFR) cetuximab (Erbitux, Bristol-Myers Squibb), or whether they received FOLFOX or FOLFIRI, results from the long-awaited Phase III CALGB/SWOG 80405 trial showed.
“ ‘What this tells us is that either FOLFIRI [folinic acid, fluorouracil and irinotecan] or FOLFOX [folinic acid, 5-fluorouracil and oxaliplatin] with either bevacizumab or cetuximab are perfectly reasonable options,’ said Alan P. Venook, MD, the Madden Family Distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco.”
Editor’s note: Researchers organized a clinical trial with volunteer patients to compare two treatments for people with metastatic colorectal cancer. All patients in the trial took a chemotherapy treatment called FOLFIRI. (FOLFIRI combines the drugs fluorouracil, leucovorin, and irinotecan.) Some of the patients were also given the drug cetuximab, and the rest took the drug bevacizumab along with FOLFIRI. The patients who took FOLFIRI plus cetuximab survived significantly longer than the patients who took FOLFIRI plus bevacizumab.
“In a European phase III FIRE-3 trial reported in The Lancet Oncology, Heinemann et al found no difference in response rate, the primary endpoint, between FOLFIRI (fluorouracil, leucovorin, and irinotecan) plus the anti-EGFR antibody cetuximab (Erbitux) vs FOLFIRI plus the anti-VEGF-A antibody bevacizumab (Avastin) in first-line treatment of patients with metastatic colorectal cancer. The cetuximab-containing regimen was associated with a significant overall survival advantage…
“In this open-label trial, 592 patients with KRAS exon 2 codon 12/13 wild-type metastatic colorectal cancer aged 18 to 75 years from centers in Germany and Austria were randomly assigned between January 2007 and September 2012 to receive FOLFIRI plus either cetuximab (n = 297) or bevacizumab (n = 295). The primary endpoint was objective response in the intention-to-treat population. The study has completed recruitment, but patient follow-up is ongoing.”
“For patients with KRAS wild-type untreated colorectal cancer, adding cetuximab or bevacizumab to combination chemotherapy offers equivalent survival, researchers said at the ESMO 16th World Congress on Gastrointestinal Cancer in Barcelona.” ‘The CALGB/SWOG 80405 trial was designed and formulated in 2005, and the rationale was simple: we had new drugs —bevacizumab and cetuximab— and the study was designed to determine if one was better than the other in first-line for patients with colon cancer,’ said lead study author Alan P. Venook, distinguished Professor of Medical Oncology and Translational Research at the University of California, San Francisco, USA.
“The CALGB/SWOG 80405 trial studied patients whose tumours were KRAS wild-type at codons 12 and 13. Patients received mFOLFOX6 or FOLFIRI at the discretion of their doctor and were randomised to cetuximab (578 patients) or bevacizumab (559 patients).
” ‘There was no meaningful difference in outcome between treatment arms,’ said Venook. ‘In both arms patients lived close to 30 months. About 10% of patients lived more than 5 years. Overall patients did much better than anticipated and it was indifferent to the type of treatment.’ ”
Editor’s note: This story discusses the results of a clinical trial that tested a treatment for colorectal cancer in volunteer patients without mutations in the KRAS gene in their tumors (as detected by molecular testing). The goal of the trial was to compare two chemotherapy drugs—bevacizumab and cetuximab—to see whether one is better than the other as a first-line colorectal cancer for so-called “KRAS wild-type” colorectal cancer. The results showed that there was no significant difference between the two.