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…
“A targeted combination therapy for patients with KRAS-mutant non-small cell lung cancer (NSCLC) did not improve overall survival (OS) or progression-free survival (PFS), researchers reported.
“The phase III, randomized SELECT-1 trial compared the experimental MEK inhibitor selumetinib, in combination with docetaxel (Taxotere), with docetaxel and placebo as second-line therapy in patients who failed a previous line of therapy, explained Pasi Jänne, MD, PhD, of the Dana Farber Cancer Institute in Boston, and colleagues.
“After a follow-up of approximately 1 year, median OS in the selumetinib combination group was 8.7 months versus 7.9 months in the docetaxel plus placebo group (hazard ratio 1.05, 95% CI 0.85-1.30, P=0.64), they wrote in JAMA.“
“AstraZeneca today announced results from the Phase III SELECT-1 trial of the MEK 1/2 inhibitor, selumetinib, in combination with docetaxel chemotherapy as 2nd-line treatment in patients with KRAS mutation-positive (KRASm) locally-advanced or metastatic non-small cell lung cancer (NSCLC).
“The results showed that the trial did not meet its primary endpoint of progression-free survival (PFS), and selumetinib did not have a significant effect on overall survival (OS). The adverse event profiles for selumetinib and docetaxel were consistent with those seen previously.”
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“AstraZeneca’s much anticipated cancer drug pipeline suffered a modest blow on Wednesday when the experimental drug selumetinib failed to meet its goal in a late-stage trial for a rare cancer of the eye.
“The drugmaker said the disappointing result in uveal melanoma would not affect other studies using the drug. Selumetinib is being investigated primarily as a treatment for advanced non-small cell lung cancer.
“Selumetinib belongs to a class of cancer drugs known as MEK inhibitors, which includes Novartis’s approved product Mekinist and the experimental compound cobimetinib from Roche and Exelixis.
“Current consensus analyst forecasts for selumetinib, which is designed for use alongside chemotherapy, point to relatively minor sales of $305 million in 2020, according to Thomson Reuters Cortellis.”
Uveal (ocular) melanoma is a difficult-to-treat type of melanoma found in the eye. Remarkably resistant to chemotherapy and prone to metastasis, it is often treated with surgery and/or radiation. Earlier this year, I wrote about new scientific findings that could lead to new targeted treatments for uveal melanoma. These would take advantage of abnormal molecular characteristics of tumor cells. Now, another targeted drug called selumetinib has entered the spotlight. It was recently tested in patients in a clinical trial with promising results. Continue reading…
“In patients with advanced uveal melanoma, treatment with the agent selumetinib, compared with chemotherapy, resulted in an improved cancer progression-free survival time and tumor response rate, but no improvement in overall survival, according to a study. The modest improvement in clinical outcomes was accompanied by a high rate of adverse events.”
Editor’s note: Selumetinib is a targeted drug that may benefit people with ocular melanoma. In a recent clinical trial to test the drug in volunteer patients, selumetinib was compared to standard chemotherapy. More patients treated with selumetinib experienced tumor shrinkage than those treated with chemotherapy, and patients treated with selumetinib experienced a longer lag time (about 4 months, compared to 2 months) before their cancer progressed. However, there was no difference in overall survival between patients treated with selumetinib and patients treated with standard chemotherapy. Unfortunately, almost all of the patients who took selumetinib experienced adverse side effects.
“Two Array BioPharma-invented MEK inhibitors, binimetinib (MEK162) and selumetinib, were showcased at the 50th annual meeting of the American Society of Clinical Oncology (ASCO). At the meeting, preliminary data for the combination of binimetinib and CDK4/6 inhibitor LEE011 (discovered by Novartis Institutes for BioMedical Research in collaboration with Astex Pharmaceuticals) from a Phase 1b/2 dose-escalation study conducted by Novartis in NRAS-mutant melanoma indicates the combination demonstrated an acceptable safety profile for most patients with promising preliminary antitumor activity. Additionally, preliminary data for selumetinib showed favorable clinical activity in pediatric patients with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs).”
Editor’s note: This article discusses a melanoma treatment that combines two durgs: binimetinib (aka MEK162) and selumetinib. A clinical trial recently found that the combo shows promise for melanoma patients whose tumors have mutations in the NRAS gene, as detected by molecular testing. Binimetinib is also being tested as a potential treatment for patients whose tumors have mutations in the BRAF gene.
Robert C, Dummer R, Gutzmer R, Lorigan P, et al. The Lancet Oncology. Jun 2, 2013.
“Patients with metastatic melanoma, 50% of whose tumours harbour a BRAF mutation, have a poor prognosis. Selumetinib, a MEK1/2 inhibitor, has shown antitumour activity in patients with BRAF-mutant melanoma and in preclinical models when combined with chemotherapy. This study was designed to look for a signal of improved efficacy by comparing the combination of selumetinib and dacarbazine with dacarbazine alone.”
Carvajal RD, Sosman JA, Quevedo F, Milhem MM, et al. 2013 ASCO Annual Meeting. Jun 2013.
“Gq/11 mutations are early oncogenic events in UM resulting in MAPK pathway activation. We demonstrated decreased viability in UM cell lines harboring Gq/11 mut with sel, a small molecule inhibitor of MEK1/2 (Ambrosini, CCR 2012).”