Most Common Lung Cancer Mutation Responds to Targeted Treatment
Editors' Recommendations
The addition of an experimental therapy that targets the most common mutation in nonsmall-cell lung cancer (NSCLC) can decrease tumor size and prolong disease-free survival, compared with standard chemotherapy alone, researchers report in a study published online November 28 in the Lancet Oncology.
The phase 2 study showed that selumetinib (AstraZeneca) and docetaxel appear to work synergistically against KRAS mutations, the genetic alteration found in 20% of patients with NSCLC, note Pasi A. Jänne, MD, PhD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues.
No approved therapies exist for KRAS-mutant NSCLC. "Although KRAS mutations were identified in lung cancer nearly 20 years ago, no approved therapies exist for KRAS-mutant NSCLC and few trials have specifically addressed this population of patients," they write. Direct inhibition of KRAS has proven clinically challenging, but selumetinib blocks KRAS indirectly through its action as a MEK1/MEK2 inhibitor.
The study involved 87 patients with histologically or cytologically confirmed staged IIIB to IV KRAS-mutant NSCLC who had failed first-line treatment.
Patients were recruited from April 2009 to June 2010. They were selected from a screened sample of 422 lung cancer patients from 67 centers in 12 countries.
All subjects received standard chemotherapy consisting of intravenous docetaxel (75 mg/m² on day 1 of a 21-day cycle) and were randomized to receive either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo.
The median duration of treatment was 117 days, with a median of 5 docetaxel cycles in the selumetinib group and 4 in the placebo group.
After a median follow-up of 7.2 months, there was no significant difference in median overall survival in the selumetinib and placebo groups (9.4 vs 5.2 months; hazard ratio [HR] for death with selumetinib, 0.8; 1-sided P = .21).
However, compared with placebo, selumetinib was associated with a significantly better response rate (37% vs 0%; P < .0001), longer progression-free survival (5.3 vs 2.1 months; 1-sided P = .014), and more progression-free survival at 6 months (37.1% vs 15.8%; 1-sided P = .016).
Response Evaluation Criteria in Solid Tumors (RECIST) were used to assess progression and response to therapy.
The most common serious adverse events, which were more frequent in the selumetinib group than in the placebo group, were neutropenia (67% vs 55%), febrile neutropenia (18% vs 0%), and asthenia (9% vs 0%). Severe dyspnea occurred less frequently in the selumetinib group than in the placebo group (2% vs 12%).
The results of this study were originally reported at the 2012 annual meeting of the American Society of Clinical Oncology, as reported by Medscape Medical News. At the time, a cancer expert endorsed the findings.
"More work is needed, but this is certainly encouraging," said Thomas Lynch, MD, from the Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut, referring to the progression-free and overall survival findings.
Dr. Jänne and colleagues acknowledge that this phase 2 study "requires further validation in a large phase 3 clinical trail to elucidate the effect on overall survival and to provide further guidance on management of the toxicity of the combination."
The new agent might also be useful in other cancers. "Our study has potential therapeutic implications for other tumors in which KRAS mutations are particularly prevalent," write the study authors, noting that KRAS mutations are found in 90% of pancreatic cancers and 40% of colorectal cancers.
The study was sponsored by AstraZeneca, the developer of selumetinib. Dr. Jänne and some of the coauthors report receiving consultancy fees from AstraZeneca and other pharmaceutical companies, and some report being employees and stockholders of AstraZeneca, as detailed in the paper.
Lancet Oncol. Published online November 28, 2012. Abstract
The phase 2 study showed that selumetinib (AstraZeneca) and docetaxel appear to work synergistically against KRAS mutations, the genetic alteration found in 20% of patients with NSCLC, note Pasi A. Jänne, MD, PhD, from the Dana-Farber Cancer Institute in Boston, Massachusetts, and colleagues.
The study involved 87 patients with histologically or cytologically confirmed staged IIIB to IV KRAS-mutant NSCLC who had failed first-line treatment.
Patients were recruited from April 2009 to June 2010. They were selected from a screened sample of 422 lung cancer patients from 67 centers in 12 countries.
All subjects received standard chemotherapy consisting of intravenous docetaxel (75 mg/m² on day 1 of a 21-day cycle) and were randomized to receive either oral selumetinib (75 mg twice daily in a 21-day cycle) or placebo.
The median duration of treatment was 117 days, with a median of 5 docetaxel cycles in the selumetinib group and 4 in the placebo group.
After a median follow-up of 7.2 months, there was no significant difference in median overall survival in the selumetinib and placebo groups (9.4 vs 5.2 months; hazard ratio [HR] for death with selumetinib, 0.8; 1-sided P = .21).
However, compared with placebo, selumetinib was associated with a significantly better response rate (37% vs 0%; P < .0001), longer progression-free survival (5.3 vs 2.1 months; 1-sided P = .014), and more progression-free survival at 6 months (37.1% vs 15.8%; 1-sided P = .016).
Response Evaluation Criteria in Solid Tumors (RECIST) were used to assess progression and response to therapy.
The most common serious adverse events, which were more frequent in the selumetinib group than in the placebo group, were neutropenia (67% vs 55%), febrile neutropenia (18% vs 0%), and asthenia (9% vs 0%). Severe dyspnea occurred less frequently in the selumetinib group than in the placebo group (2% vs 12%).
The results of this study were originally reported at the 2012 annual meeting of the American Society of Clinical Oncology, as reported by Medscape Medical News. At the time, a cancer expert endorsed the findings.
"More work is needed, but this is certainly encouraging," said Thomas Lynch, MD, from the Yale Cancer Center and Smilow Cancer Hospital in New Haven, Connecticut, referring to the progression-free and overall survival findings.
Dr. Jänne and colleagues acknowledge that this phase 2 study "requires further validation in a large phase 3 clinical trail to elucidate the effect on overall survival and to provide further guidance on management of the toxicity of the combination."
The new agent might also be useful in other cancers. "Our study has potential therapeutic implications for other tumors in which KRAS mutations are particularly prevalent," write the study authors, noting that KRAS mutations are found in 90% of pancreatic cancers and 40% of colorectal cancers.
The study was sponsored by AstraZeneca, the developer of selumetinib. Dr. Jänne and some of the coauthors report receiving consultancy fees from AstraZeneca and other pharmaceutical companies, and some report being employees and stockholders of AstraZeneca, as detailed in the paper.
Lancet Oncol. Published online November 28, 2012. Abstract
.png)
No hay comentarios:
Publicar un comentario