Crizotinib Treatment in ROS1-positive NSCLC Patients: A Case Study
Mark A. Socinski, MD
The patient is a 52-year-old man who was diagnosed, in 2004, with stage 1 adenocarcinoma of the lung before undergoing a right middle lobe lobectomy. He did not receive adjuvant therapy.
The patient subsequently relapsed in 2007 and was treated with carboplatin, docetaxel, and velcade as first line agents while enrolled in a clinical trial. His disease progressed.
He was subsequently treated with Tarceva (erlotinib) as a second line therapy for about 10 months. His disease subsequently progressed and he was treated with pemetrexed as a third line therapy. He had a minor response, and after six cycles, he was given a drug holiday.
Prior cytogenetic testing for various cytogenetic abnormalities including KRAS, EGFR, and ALK, were negative. Since the other markers were negative, in October, 2011, his original tumor, which had been preserved, was tested for ROS1 using fluorescence in situ hybridization (FISH). His tumor was positive. At that time, he had been on a six-month hiatus from treatment.
His disease progressed and his tumor had increased in size. The patient was treated with pemetrexed again for two cycles with no response; in fact, he had a declining performance status (PS) and radiographic evidence of disease progression. His clinical course was further complicated by borderline renal function exacerbating the toxicity of pemetrexed; treatment with pemetrexed was terminated in December 2011.
In January, 2012, because of his declining PS, the patient considered hospice care. He was largely wheelchair bound, oxygen dependent, and had experienced significant weight loss. In February, 2012, he was treated with crizotinib (250mg po bid).
The patient had been previously diagnosed with a mildly long QTC interval, was under the care of a cardiologist and taking cardiac medications. One of the warnings about crizotinib is that it can lengthen the QTC interval. Prior to taking crizotinib, the patient's cardiologist had to adjust the dosage of his cardiac medications.
The patient has received two cycles (each cycle is four weeks in duration) of crizotinib and has had rapid signs of clinical improvement.
Shortly after initiating crizotinib, the patient was no longer oxygen-dependent and had a significant improvement in both appetite and performance status gaining approximately 10 pounds over the first month of treatment. A CT scan repeated six weeks after initiation of crizotinib demonstrated improvement in his pleural disease and his liver metastases. He continues on crizotinib at the current time.
The ROS1 rearrangement has only recently been discovered and identified as a driver of oncogenesis in a small percentage of the lung cancer patient population. ROS1 is just one of several cytogenetic abnormalities found in NSCLC and is an example of the increasing complexity of molecular heterogeneity found in these tumors.
The most common molecular findings are KRAS mutations, EGFR mutations, and EML4-ALK translocations, which account for approximately 50% of all cytogenetic abnormalities detected in NSCLC. Less common molecular findings include ROS1 rearrangements, HER2 mutations, c-Met mutations, Raf mutations, PI 3-Kinase mutations, ect.
The prevalence of ROS1 is estimated to be approximately 1.7% in NSCLC patients, whereas ALK positivity is more prevalent at approximately 2.9%. ROS1 is also an oncogene translocation and shares a fair amount of sequence homology with ALK.