VIENNA—Highly anticipated details from the Phase III PROFILE-1007 trial showed that crizotinib more than doubled the progression-free survival (PFS) time compared with pemetrexed or docetaxel chemotherapy in previously treated patients with anaplastic lymphoma kinase (ALK)-positive advanced non-small cell lung cancer (NSCLC).
In the study, reported here at the European Society for Medical Oncology Congress (Abstract LBA-1), patients who received crizotinib had a median progression-free survival time of 7.7 months versus 3.0 months for those who received single-agent chemotherapy, as assessed by independent radiologic review.
This translated to a significant 51 percent reduction in the risk of progression in the crizotinib arm, according to the late-breaking report presented during the Presidential Symposium. When looked at individually, the median PFS time was 4.2 months for patients on pemetrexed and 2.6 months for patients on docetaxel, said the principal investigator, Alice T. Shaw, MD, PhD, Assistant Professor in the Department of Medicine at Harvard Medical School and Attending Physician in the Thoracic Cancer Program at Massachusetts General Hospital.
Subgroup analyses, including those performed by age, gender, ethnicity—i.e., whether Asian or non-Asian—smoking status, and the presence or absence of brain metastases, consistently favored crizotinib, she said. The overall response rate, as assessed by independent radiologic review, was also significantly higher in the crizotinib arm: 65.3 vs. 19.5 percent for chemotherapy. The overall response rates were 29.3 percent with pemetrexed and 6.9 percent with docetaxel.
Moreover, crizotinib was associated with significant improvement in lung cancer symptoms and quality of life compared with chemotherapy, she said. The study demonstrates that crizotinib “absolutely should be standard of care for all ALK-positive patients.”
U.S. vs. Europe
The ALK mutation is found in about three to five percent of lung cancers, with younger patients and non-smokers disproportionately affected, Shaw noted.
In August 2011, the FDA granted accelerated approval to crizotinib based on an overall response rate of about 60 percent in 255 patients with ALK-positive NSCLC patients treated with the drug in two early-phase trials, both reported at that year's ASCO Annual Meeting (Abstract 2501 and Abstract 7514).
In June, Pfizer announced that the Phase III PROFILE-1007 trial had met its primary endpoint, with crizotinib significantly improving progression-free survival compared with chemotherapy and that details would be reported at ESMO 2012. Throughout this time, Europe has held back approval, with regulatory agencies maintaining that the detailed data from the randomized trial are needed to reach a decision.
Wait, was that laughter? Indeed it was, as the Discussant, Jean-Charles Soria, MD, PhD, Professor of Medicine and Medical Oncology at Paris University XI, struck just the right chord for his mostly European audience: “While the U.S. treats, Europe randomizes.”
In fact, the (European) Committee for Medicinal Products for Human Use (CHMP) recently gave crizotinib a positive recommendation, reportedly because it was given the results of PROFILE-1007 in advance of the Congress.
And not surprisingly, a quick survey of a handful of attendees showed that they predicted that the study not only would be followed quickly by European Medicines Agency approval, but would also be practice-changing there.
ESMO Press Officer Fortunato Ciardiello, MD, Assistant Professor of Medical Oncology at Seconda Univesrità degli Studi di Napoli, said, “These data will tell me that if I am treating a patient second-line, the best option is crizotinib. And it gives us a little more information on the toxicity profile. These are strong, important data.”
ALK is a tyrosine kinase target in several types of cancer. In NSCLC, ALK is activated by chromosomal rearrangement, leading to constitutive kinase activation and oncogene addiction—molecular speak for the fact that the cancer cell then needs ALK activation to survive, Shaw said.
Crizotinib is an orally available, small-molecule tyrosine kinase inhibitor (TKI) targeting ALK, ROS1, and MET. And although the early data were not sufficient for approval in Europe, studies have consistently shown crizotinib has clinical activity in advanced ALK-positive NSCLC. In contrast, the activity of standard chemotherapy as first-line therapy in ALK-positive NSCLC is uncertain.
In unselected patients (with unknown ALK status), single-agent chemotherapy as second-line had limited efficacy in NSCLC patients, she said. The researchers therefore hypothesized that in a prospective, randomized trial, crizotinib would have superior efficacy to standard second-line chemotherapy in patients with advanced ALK-positive NSCLC.
The trial involved 347 patients at 105 sites in 21 countries randomized in a 1:1 fashion to receive oral crizotinib at 250 mg twice a day, in a 21-day cycle, or chemotherapy with either pemetrexed at 500 mg/m2 or docetaxel at 75 mg/m2 IV on Day 1 of a 21-day cycle, as second-line therapy for ALK-positive NSCLC.
For the 174 patients in the chemotherapy arm, the treating physicians chose pemetrexed for 99 patients, docetaxel for 72, and no chemotherapy for the other three patients. Treatment could be continued beyond disease progression if a patient had ongoing clinical benefit.
The duration of follow-up was a median of about 12 months in both arms. But the number of cycles of therapy differed substantially: a median of 11 cycles in the crizotinib arm vs. four cycles in the chemotherapy arm.
This may partially explain the greater number of deaths due to any cause in crizotinib-treated patients: 25 any-cause vs. seven any-cause among patients treated with chemotherapy, she noted.
The data were not mature enough to determine whether there is an overall survival advantage with crizotinib, and even when the data are mature, there may not be a survival advantage because of an extremely high crossover rate of control patients to the targeted drug, Shaw said.
An interim analysis of overall survival rates showed absolutely no difference in the Kaplan-Meier curves between the chemotherapy and crizotinib arms. A total of 87 percent of patients in the chemotherapy arm crossed over to crizotinib, “so you are comparing two populations of patients who pretty much received crizotinib.”
For now, the data show that patients on crizotinib lived a median of 20.3 months, compared with 22.8 months for patients treated with chemotherapy.
Soria said he also was not concerned with the lack of proof of a survival benefit: “Historical data from two years ago showed pemetrexed led to a 9.3-month improvement in overall survival, and this is 22 months. So, this is really changing the natural history of the disease.”
“There is no doubt we can say we have here a clear and strong signal of activity.”
The fact that side effects were substantially greater with crizotinib than with chemotherapy may at first seem worrisome, but are actually not, Shaw said. Patient-reported outcomes—including global quality of life and physical, emotional, cognitive, and social functioning—and patient-reported time to deterioration in lung cancer symptoms both favored crizotinib treatment.
“Duration on study treatment was quite a bit longer with crizotinib than with chemotherapy—more than twice as long. So, those patients had more time to accumulate toxicities. And more patients continued on crizotinib after progression. The analysis so far has not taken that into account, but we will do an analysis like that,” she said.
As far as patient-reported symptom outcomes, those treated with crizotinib reported greater improvements from baseline in cough, dyspnea, fatigue, alopecia, insomnia, and pain, compared with chemotherapy-treated patients. All the differences reached statistical significance, she said. The median time to deterioration of symptoms in patients on crizotinib was 5.6 months versus only 1.4 months in the chemotherapy group.
As far as side effects, patients in the crizotinib arm were more likely to have visual disturbances, diarrhea, nausea, vomiting, elevated transaminases, edema, upper respiratory infections, and dizziness. Patients in the chemotherapy arm had more fatigue, alopecia, dyspnea, and rash.
“The majority of the adverse events with crizotinib were Grade 1–2. Nausea and vomiting are more common with crizotinib, but if you look closely, you can see that the use of anti-nausea medications, including steroids, was much higher in the chemotherapy group. So, it gives you a sense that this checklist doesn't capture the intensity of the side effects. We need to go back and do more analyses,” Shaw said.
Soria agreed that there is no real toxicity issue with crizotinib: “Toxicity appears high, but it is not adjusted for duration of therapy. There is some visual disturbance, but it is acceptable. There is a risk of liver toxicity—Grade 3 to 4 is 16 percent—and there are some rare side effects such as renal cysts that clinicians need to be aware of,” he said.
Asked about the visual disturbances with crizotinib, Shaw said, “They are mild. Patients don't report a visual disturbance unless you ask about it. Now, in practice if we ask about it, about 80 percent of patients report it. But there are no discontinuations due to visual disturbances. It is a dark-to-light adaptation issue that lasts about 30 seconds. It is almost a biomarker for the drug.”
The next step, experts here said, is getting more lung cancer patients tested for the ALK mutation. That means educating physicians, patients, regulators, and insurers, but progress is being made.
As use of crizotinib increases, so too will financial and practical issues surrounding implementation of molecular testing in daily practice, Soria added.
In the U.S., testing is starting to catch on, and insurance companies generally pay for it. In France, 28 testing sites have been established throughout the country, making a panel of 14 genetic tests available to cancer patients at no cost to doctors, patients, or hospitals.
One of many gathered around the podium after the session, a Dutch pathologist said that only about half of the patients who should be tested are being tested in his country. A U.S. oncologist chimed in: “We are jealous of the situation in France. We are nowhere near having as many people tested [percentage-wise] in the U.S. The tests are now in the guidelines, but it is important to tell doctors, to show them it makes a difference.”
As well as crizotinib works, patients still develop resistance to it, and with increasing use, there will be more resistance, Shaw said. There are several next-generation ALK-inhibitors in development that “show very promising activity” and may help to combat that problem.