Diagnosis of adenocarcinoma of the lung, a major subtype of non-small lung cancer (NSCLC), nowadays triggers mandatory testing of tumor tissue for alterations in four genes: EGFR, ALK, ROS1, and more recently, BRAF. If present, these alterations predict sensitivity to specific targeted drugs approved by the U.S. Food and Drug Administration (FDA) that work better and often longer than standard chemotherapy, and are better tolerated.
However, there are many more targetable/actionable genomic alterations (also known as “drivers”) in NSCLC. This blog post will briefly discuss most of them, with the goal of promoting molecular testing for more than the four “usual suspects” mentioned above. Some patients with these alterations may benefit from FDA-approved drugs or from enrollment in clinical trials that are testing additional drugs and drug combinations. Continue reading…
“Ceritinib appeared safe and effective in patients with ROS1–rearranged non–small cell lung cancer, according to a multicenter, open-label phase 2 study.
“ALK inhibitors — especially crizotinib (Xalkori, Pfizer) — effectively treat ROS1–positive cell lines and tumors. However, patients eventually develop resistance and experience a high incidence of brain recurrence.
” ‘Treatment options beyond crizotinib are needed, and clinical development of other ROS1 inhibitors should be accelerated to improve treatment outcome of patients with ROS1–positive NSCLC,’ Byoung Chul Cho, MD, PhD, assistant professor at Yonsei Cancer Center of Yonsei University College of Medicine, and colleagues wrote.”
“On May 26, 2017, the U.S. Food and Drug Administration granted regular approval to ceritinib (ZYKADIA, Novartis Pharmaceuticals Corp.) for patients with metastatic non-small cell lung cancer (NSCLC) whose tumors are anaplastic lymphoma kinase (ALK)-positive as detected by an FDA-approved test.
“In April 2014, ceritinib received accelerated approval for patients with ALK-positive metastatic NSCLC whose disease has progressed or who are intolerant to crizotinib based on a blinded independent review committee (BIRC)-assessed overall response rate (ORR) of 44% among 163 patients in a single-arm trial.”
“The FDA has granted a priority review to ceritinib (Zykadia) as a first-line treatment for patients with ALK-positive, metastatic non–small cell lung cancer (NSCLC), according to Novartis, the manufacturer of the second-generation ALK inhibitor.
“The priority review is based on findings from the phase III ASCEND-4 trial, in which ceritinib reduced the risk of disease progression or death by 45% compared with standard chemotherapy. The median progression-free survival (PFS) benefit favoring ceritinib was 8.5 months (HR, 0.55; 95% CI, 0.42-0.73; P <.001).”
“Ceritinib provides longer progression-free survival than chemotherapy in crizotinib-pre-treated patients with non-small-cell lung cancer harbouring an ALK rearrangement, according to results of the phase III ASCEND-5 study presented at the ESMO 2016 Congress in Copenhagen.
” ‘Patients with non-small cell lung cancer (NSCLC) should receive front line therapy with the anaplastic lymphoma kinase (ALK) inhibitor crizotinib,’ said lead author Professor Giorgio Scagliotti, head of the Department of Oncology, University of Turin, Italy. ‘Most patients develop resistance to crizotinib and currently second line treatment is represented by chemotherapy alone.’ ”
“Updated results of the phase I ASCEND-1 trial, reported by Kim et al in The Lancet Oncology, indicate that the ALK inhibitor ceritinib (Zykadia) produced high response rates in advanced ALK-rearranged non–small cell lung cancer (NSCLC), including intracranial disease, in both patients with and without prior ALK inhibitor treatment.
“In the open-label trial, 246 patients enrolled from 20 sites in 11 countries in Europe, North America, and Asia-Pacific between January 2011 and July 2013 received oral ceritinib at 750 mg/d. Patients had ALK-rearranged locally advanced or metastatic disease that had progressed despite standard therapy or for which there was no effective standard therapy. A total of 83 patients had received no prior ALK inhibitor treatment, and 163 had received crizotinib (Xalkori), with 5 also receiving alectinib (Alecensa) after crizotinib. In these two groups, 53% and 54% of patients were female, 58% and 66% were white, and 42% and 29% were Asian.”
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“The use of drugs that target genetic mutations driving the growth of tumors has revolutionized treatment for several serious forms of cancer, but in almost every case, tumors become resistant to the drugs’ therapeutic effects and resume growth, often through the emergence of new mutations, which has spurred the development of more powerful drugs that can overcome resistance mutations. In the Dec. 24 issue of New England Journal of Medicine, Massachusetts General Hospital (MGH) physicians report their study examining the evolution of drug resistance in a lung cancer patient treated with multiple different targeted therapies. When resistance developed to the third targeted therapy, the new mutation actually restored the cancer’s response to the very first targeted therapy drug used to treat the patient.”
“Novartis announced today that the Committee for Medicinal Products for Human Use (CHMP) of the European Medicines Agency adopted a positive opinion for Zykadia® (ceritinib) to treat adult patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC) previously treated with crizotinib. If approved in the European Union (EU), Zykadia will be the first treatment option to address an unmet medical need for patients with ALK+ NSCLC previously treated with crizotinib.
” ‘Patients with advanced ALK+ NSCLC have few options when their cancer does not respond to currently approved therapy,’ said Alessandro Riva, MD, Global Head, Novartis Oncology Development and Medical Affairs. ‘As a leader in the development of precision oncology medicines, Novartis is committed to developing and bringing to market new treatments for patients with ALK+ NSCLC. This positive CHMP opinion for Zykadia brings us one step closer to providing the lung cancer community with new hope in the fight against this terrible disease.’
“Each year, there are 1.6 million people diagnosed with lung cancer, the leading cause of cancer death worldwide. The most common type of lung cancer is NSCLC, accounting for 85-90% of all cases. Of those, 2-7% are driven by a rearrangement of the ALK gene, which increases the growth of cancer cells and can be identified by a molecular test of the cancer tumor. Despite significant treatment advances for patients with ALK+ NSCLC, disease progression is often inevitable and more treatment options are needed.”
The gist: Two patients with lung cancer may have distinctly different tumors that make them respond differently to the same treatment. Oncologists can use molecular tests to determine which treatments might work for which patients. These molecular tests find genetic mutations in tumors. These mutations can be targeted with specific targeted drugs. However, tumors can develop new, additional mutations that make them resistant to targeted drugs. Recent research looked at mutations that cause resistance to a drug called alectinib. (Alectinib is meant to treat tumors with mutations in the ALK gene.) The researchers identified mutations that were causing the resistance, and identified two drugs, ceritinib and AP26113, that could be used as alternatives for patients resistant to alectinib. Indeed, one patient who was resistant to alectinib was successfully treated with ceritinib.
“Two mutations that cause lung cancer resistance to the investigational ALK inhibitor alectinib were identified, and this information may help design new treatment regimens for patients with ALK-positive lung cancer, according to a study published in Clinical Cancer Research, a journal of the American Association for Cancer Research.
“In 2014, more than 159,000 men and women are expected to die of lung cancer in the United States. About 84 percent of lung cancers are non-small cell lung cancers (NSCLC), and 3 to 5 percent of NSCLCs have mutations in the gene ALK.
” ‘The goal of our study was to determine why ALK-positive lung cancers become resistant to alectinib, and we looked at this in two different ways,’ said Alice T. Shaw, MD, PhD, a thoracic oncologist at the Massachusetts General Hospital Cancer Center. ‘We studied a resistant cell line model that we generated in the lab, and we also studied a tumor sample from a patient with NSCLC who had been treated with alectinib and then became resistant.
” ‘We discovered two novel mutations that have not been described before in patients with NSCLC, and these mutations conferred high-level resistance to alectinib,’ Shaw added. ‘Another equally important finding from this study is that we were able find a way to overcome this type of resistance, in our laboratory experiments as well as in a patient, using another next-generation ALK inhibitor, ceritinib, previously known as LDK378.’ “