The U.S Food and Drug Administration (FDA) has granted regular approval to the drug crizotinib (Xalkori) for the treatment of advanced non-small cell lung cancer (NSCLC) in patients who have mutations in the ALK gene. Xalkori received accelerated approval for this application in August 2011. Regular approval was awarded based on the results of a study examining patients with advanced NSCLC whose cancer had progressed despite first-line chemotherapy. Patients treated with Xalkori went an average of 7.7 months without further cancer worsening, compared to 3.0 months in those receiving the chemotherapy agents pemetrexed (Alimta) or docetaxel (Taxotere). Tumors shrank in 65% of the Xalkori-treated patients, compared to 20% with Alimta or Taxotere. However, overall survival did not differ between the Xalkori group and the chemotherapy group.
The U.S. Food and Drug Administration (FDA) has granted breakthrough therapy designation for a lung cancer treatment called alectinib, made by Roche. The designation was based on new data presented at the European Cancer Congress (ECC). Alectinib is reported to be effective in patients with non-small cell lung cancer (NSCLC) with mutations in the ALK gene. Imporantly, tumor shrinkage was seen in patients whose cancer worsened on crizotinib (Xalkori), the currently approved drug for this subgroup of patents.
The UK’s National Institute for Health and Clinical Excellence (NICE) confirmed its decision to reject using National Health Service funding to provide crizotinib (Xalkori) to patients. Xalkori is used for patients with previously treated non-small cell lung cancer (NSCLC) who have mutations in the ALK gene. While NICE acknowledges that Xalkori is effective in these patients, they do not consider its benefit substantial enough to warrant its high cost. Xalkori has been found to extend the time without cancer progression by an average of 5.1 months compared to standard chemotherapy; it is unclear whether it increases overall survival. UK patients can still take Xalkori, but would have to pay the full cost themselves (£37,512 – £51,579 for a complete treatment course).
Xalkori (crizotinib) is very effective for most non-small cell lung cancer (NSCLC) patients with mutations in the ALK gene. However, new evidence suggests that current criteria for ALK mutation may be missing patients who could be treated with Xalkori. A recent study of NSCLC patients found that 8.5% had tumors that contained more than 10% cells with ALK mutations, but less than 15%, the current cut-off for ‘ALK-positive’ lung cancer. These patients may benefit from Xalkori or other ALK inhibitors. Moreover, some patients have atypical ALK mutations that are not detected by the standard test. A patient with such atypical ALK mutations profiled in a recent case study responded well to Xalkori treatment.
In 2008, Dr. Charles Sawyers, currently the president of American Association for Cancer Research, wrote an article for the journal Nature entitled: ‘The Cancer Biomarker Problem.’ This excellent paper clearly explains what cancer biomarkers are, outlines the different categories of biomarkers, and emphasizes how important biomarkers are in the field of targeted therapies. Predictive biomarkers are indispensable tools that should direct the rational use of targeted drugs in cancer patients. There are additional types of biomarkers, including some that could help evaluate the course of cancer progression or help determine the effective dose of an investigational drug. But this post focuses on predictive biomarkers. Continue reading…
In an ongoing phase I clinical trial, the new lung cancer drug LDK378 showed signs of effectiveness in advanced non-small cell lung cancer (NSCLC) with mutations in the ALK gene. Sixty percent of the patients treated with the highest dose of LDK378, which blocks ALK, benefited from the drug. These effects were seen both in patients who had never been treated with the ALK inhibitor crizotinib (Xalkori) before and patients who had become resistant to Xalkori. LDK378 was declared a Breakthrough Therapy by the FDA in March, a designation intended to expedite the development and approval process of treatments for life-threatening conditions. Novartis, which produces LDK378, is initiating two phase II clinical trials (one examining patients who were previously treated with chemotherapy and Xalkori, the other patients with no history of Xalkori treatment) and planning a forthcoming phase III trial.
Crizotinib (Xalkori) is an effective treatment for lung cancer patients with mutations in the ALK or the ROS1 gene. However, patients usually develop resistance to the drug after some time. A patient with advanced non-small cell lung cancer (NSCLC) with a ROS1 mutation improved significantly at first after enrolling in a clinical trial assessing Xalkori. However, after 3 months, her cancer again began to worsen despite continued Xalkori treatment. Genetic testing revealed that she had developed a new, additional mutation in the ROS1 gene that makes cells more resistant to Xalkori. The new mutation was present in all of the tumors that had stopped responding to the drug. A better understanding of the way in which cancer cells develop resistance to targeted therapies is critical for developing new treatments that can overcome drug resistance.
Crizotinib (Xalkori) may be more beneficial than chemotherapy for patients with advanced non-small cell lung cancer (NSCLC) who have a mutation in the ALK gene, a phase III clinical trial found. The patients had previously been treated with chemotherapy, after which their cancer had started to progress again. During the trial, they received either a different chemotherapy agent or Xalkori. Xalkori-treated patients went on average 7.7 months without a worsening of their cancer, compared to 3.0 months in the chemotherapy-treated patients. Patients on Xalkori also experienced better quality of life. This study demonstrates the importance of genetic testing for biomarkers, such as ALK mutation, and prescription of targeted therapies based on these biomarkers.
Many patients with non-small cell lung cancer (NSCLC) who have mutations in the ALK gene benefit from treatment with ALK inhibitors. A phase I/II clinical trial of the new ALK inhibitor CH5424802 determined that the drug was well tolerated and showed signs of effectiveness. Out of 46 patients with ALK-mutant advanced NSCLC, 2 experienced a complete response and 41 a partial response; 40 patients currently remain on the treatment. If future studies confirm the effectiveness of CH5424802, it could offer an additional option to crizotinib (Xalkori), currently the only ALK inhibitor approved for treating ALK-mutant NSCLC. An ongoing clinical trial is investigating whether CH5424802 is beneficial in patients who have become resistant to Xalkori.