July 12, 2011 —Crizotinib, a new targeted drug aimed at certain patients with nonsmall-cell lung cancer (NSCLC), is expected to be approved before the end of the year. The drug targets an ALK rearrangement, which is found in about 4% to 5% of patients with NSCLC; in these patients it has shown striking activity and appears to prolong survival.
"Crizotinib may prolong survival and fundamentally alter the natural history of ALK-positive nonsmall-cell lung cancer," said Alice Shaw, MD, from Massachusetts General Hospital in Boston. She was presenting a comparison of data from a phase 1 trial with historic controls last week at the 14th World Conference on Lung Cancer (WCLC) in Amsterdam, the Netherlands; the data were previously reported at the annual meeting of the American Society of Clinical Oncology (ASCO).
Data from phase 1 and 2 clinical trials of crizotinib have already been filed for accelerated approval with the US Food and Drug Administration; phase 3 studies are ongoing. The accelerated approval was filed in May 2011, and has to be processed within 6 months, so a decision is likely in November 2011, if not before. The same data have been filed in Japan.
A companion diagnostic has been developed and will be launched soon. The Abbott ALK FISH test uses fluorescence in situ hybridization, the standard method for identifying ALK rearrangements in NSCLC tumors, to identify patients who could benefit from crizotinib therapy. The test was introduced in Europe last week, and is in the process of registration across the world, including Australia, Southeast Asia, and the United States.
Small Percentage, But Large Numbers
Although ALK rearrangement is only found in a small portion of NSCLC patients, because lung cancer is so common, the number of patients who stand to benefit is substantial — 4% to 5% of all patients with NSCLC is about 8,000 to 10,000 patients each year in the United States, Dr. Shaw pointed out. This compares with around 5,000 to 6,000 patients each year in the United States who are diagnosed with chronic myeloid leukemia and treatable with the targeted agent imatanib (Gleevec).
Globally, there are an estimated 40,000 patients each year diagnosed with ALK-positive NSCLC, Dr. Shaw noted.
"In these patients, crizotinib will become the standard treatment," Dr. Shaw told Medscape Medical News. The data so far have come mainly from patients who have previously been treated with chemotherapy, but patients who receive crizotinib as first-line therapy do even better, she said in an interview.
Most oncologists would use crizotinib in any line in patients with an ALK rearrangement.
"No matter what labeling is approved, most oncologists would use crizotinib in any line in patients with an ALK rearrangement," she reported.
"You should use the most effective therapy first," Dr. Shaw said. "You wouldn't put such a patient on chemotherapy first, as you may lose the opportunity for that patient to go on crizotinib."
New data for EGFR inhibitors in patients with EGFR-positive NSCLC, also presented at the WCLC, show that these drugs are effective whether they are used as first-, second-, or third-line therapy.
The success of crizotinib shows that the EGFR story is not "a one-hit wonder," said Mark Kris, MD, chief of the thoracic oncology service at Memorial Sloan-Kettering Cancer Center in New York City. This is another mutation, and another targeted therapy, yet the result is the same — much better responses and better outcomes in that section of the patient population, he said. "It proves that this is the right approach to be taking," he noted, and validates the efforts going into the Lung Cancer Mutation Consortium, which he is heading.
When patients respond to a targeted therapy, the responses can be dramatic. "It depends on the severity of the symptoms, but some patients respond very quickly," Dr. Shaw told Medscape Medical News. "Within days they are breathing better, and within a week they say they are feeling incredibly better," she said. Many of these patients are in their 30 or 40s, and they don't recognize how fatigued they have become; however, with the drug, they report having more energy and "feeling so much better than before," she said. "This is not something that we see with chemotherapy, where patients feel even more tired," she added.
"Not all patients respond, but about 90% do," Dr. Shaw said, and it can be quite obvious to the clinician who is responding.
The 10% of patients who do not respond are known as "intrinsically resistant"; this is also seen with the EGFR inhibitors, where again about 10% of EGFR-positive NSCLC patients not respond, she added.
Although the responses to targeted therapy can be dramatic, it has proven difficult to collect definitive data showing an improvement in outcome. The data with the EGFR inhibitors so far show a statistically significant improvement in progression-free survival, but the results for overall survival have not reached statistical significance, mainly because of a high crossover in these trials, experts say. Any patient in the control group who progresses is immediately offered the targeted therapy, confounding the outcomes.
"All of the patients in these trials are doing well," said Roy Herbst, MD, PhD, chief of medical oncology at the Yale Cancer Center in New Haven, Connecticut. Comparisons with historic controls suggest a survival advantage, he told Medscape Medical News. Prior to the advent of the EGFR inhibitors, patients with advanced NSCLC treated with chemotherapy had a median overall survival of around 8 to 9 months, Dr. Herbst said. Now, patients with EGFR mutations treated with erlotinib have a median overall survival of around 18 to 20 months, he said. However, some patients respond very well and can live for several years, he added, noting that he has a few patients who are still alive at 8 to 9 years.
Going forward, collecting data to show a survival advantage will be an ongoing problem. It would be unethical to not offer the targeted therapy as a crossover, so future trials will have similar confounding.
There are 2 ongoing phase 3 studies with crizotinib, both aiming to enroll just over 300 patients. One study is comparing first-line crizotinib with pemetrexed used together with cisplatin or carboplatin; the other is comparing second-line crizotinib with pemetrexed or docetaxel. In both cases, patients enrolled in the trial are ALK-positive, and those in the chemotherapy groups are offered crossover to crizotinib as soon as they progress.
Comparison With Historic Controls
To offer some way around the problem, Dr. Shaw presented an analysis of survival data from a phase 1 comparison with historic controls.
The results from the phase 1 trial have already been published (N Engl J Med. 2010;363:1693-1703). That study enrolled 82 patients with ALK-positive NSCLC, and showed that crizotinib had marked activity, Dr. Shaw reported. An objective response rate was documented in 57% of patients, stable disease was documented in 33% of patients, and median progression-free survival was 10 months. The median overall survival has not yet been reached, Dr. Shaw explained. At a median of 18 months of follow-up, 61% of patients are still alive, so median 1-year survival is 74% and median 2-year survival is 54%.
For their study, Dr. Shaw and colleagues excluded some of the patients in this trial who came from Korea, and included only 56 patients from the United States and Australia, so that the cohort was comparable to the patients in the 2 control groups. This comprised a population of 36 patients from the United States and Australia who were ALK-positive but were not enrolled in the trial, for a variety of reasons, and a population of 253 outpatients from the Massachusetts General Hospital who were ALK-negative.
To minimize skewing by heavily pretreated patients, Dr. Shaw and colleagues focused in each of these groups on patients who had received second-line therapy and on patients who had never smoked, or smoked only lightly, and had adenocarcinoma.
From the phase 2 trial, this left 30 patients who had received crizotinib as second- or third-line therapy; in this group, the median overall survival has not been reached, but 1-year survival is 70% and 2-year survival is 55%.
This is significantly better than what is seen in the ALK-positive control group, Dr. Shaw reported. Here, among the 23 patients who received second-line therapy, the median overall survival was 6 months, the 1-year survival was 44%, and the 2-year survival was 12%. The difference between this group and those who received crizotinib was highly statistically significant, with a hazard ratio of 0.36 (P = .004), she said.
In comparison, patients in the other control group who were ALK-negative (and also EGFR-negative) had a median survival of 11 months, a 1-year survival of 47%, and a 2-year survival of 32%; this was not statistically significant (hazard ratio, 1.42; P = .18). This suggests that having the ALK rearrangement in itself does not affect outcome, and without crizotinib treatment, patients who are ALK-positive are similar to lung cancer patients without mutations, Dr. Shaw explained.
The major limitation of this study is that it is a retrospective nonrandomized analysis, with unmatched patient populations, Dr. Shaw noted. In addition, the number of patients in each group is small.
Despite these limitations, "Dr. Shaw's study is significant," said Ramaswamy Govindan, MD, from the Alvin J. Siteman Cancer Center at the Washington University School of Medicine, St. Louis, Missouri, who acted as discussant at the ASCO annual meeting.
"One thing is quite clear — if you give targeted drugs to targeted patients, they do quite well," Dr. Govindan concluded.
ALK in Other Tumors
Crizotinib may yet find a role in cancers other than NSCLC, because the ALK rearrangement has been found in several other tumors. These include a very rare type of sarcoma, inflammatory myofibroblastic tumor, anaplastic large cell lymphoma, and a type of pediatric neuroblastoma. There are 2 ongoing open-label clinical trials offering crizotinib therapy to patients with tumors who are found to carry the ALK rearrangement.
The phase 1 trial with crizotinib was sponsored by Pfizer. Dr. Shaw has disclosed no relevant financial relationships. Dr. Kris reports serving as a consultant for Boehringer Ingelheim, Pfizer, and Chugai. Dr. Govindan reports receiving honoraria from AstraZeneca, GlaxoSmithKline, and Taiho. Dr. Herbst reports serving on the advisory committee for Amgen, Biothera, Genetics Squared, Med Trust, N of One, SynDevRx, Targeted Molecular Diagnostics, and Diatech.
14th World Conference on Lung Cancer (WCLC): Abstract 031.06. Presented July 6, 2011.
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