It was “fight night” at the 2017 American Society of Clinical Oncology annual meeting, with two big bouts between lung cancer therapies. In the ARCHER 1050 trial, up-and-comer dacomitinib took on the seasoned gefitinib (Iressa) in patients with advanced, EGFR-mutated non-small cell lung cancer (NSCLC). In the ALEX trial, the matchup was between alectinib (Alecensa) and crizotinib (Xalkori) in patients with treatment-naive, advanced ALK-positive NSCLC.
Which targeted therapies came out on top in these phase III trials?
ARCHER: Win by Decision
“Dacomitinib is a second-generation tyrosine kinase inhibitor [TKI] … and being second generation implies two clinical features,” explained the lead investigator, Tony Mok, MD, of the Chinese University of Hong Kong. “First it forms an irreversible bond with the receptor. Second, it [has] pan ErbB inhibition with HER1, HER2, and HER4.”
Based on positive findings from the ARCHER 1017 trial, “we thought it is likely … that dacomitinib would be superior to gefitinib, a first-generation TKI, in terms of PFS,” he added.
Mok’s group found that treatment with dacomitinib extended the time to relapse or death by 41% compared with standard gefitinib therapy.
The team randomly assigned 452 previously untreated patients with stages IIIB or IV NSCLC to receive 45 mg of dacomitinib a day or 250 mg of gefitinib a day.
Mok noted that the patients with central nervous system (CNS) metastases were not included in the study population. “The reason is we were not certain of the penetration of dacomitinib to the CNS at the time the study was designed,” he explained, adding that the role of gefitinib in CNS metastases is also unknown.
As for the ASCO presentation, 136 patients given dacomitinib and 179 given gefitinib had either progressed (59.9%) or died (79.6%). The median PFS for patients on dacomitinib was 14.7 months versus 9.2 months for gefitinib. The hazard ratio for progression was 0.59 in favor of dacomitinib.
The ORR for the study drug was 74.9% versus 71.6% for gefitinib. However, Mok reported that the duration of response was significantly longer for dacomitinib, at 14.8 months versus 8.3 months. OS data was not mature at the time of presentation, he added.
While dacomitinib may have won the overall “fight,” the agent was down for the count when it came to toxicity. Adverse events were as follows for dacomitinib compared with gefitinib:
- Diarrhea: 87.2% versus 55.8%
- Paronychia: 61.7% versus 20.1%
- Dermatitis acneiform: 48.9% versus 28.6%
- Stomatitis: 43.6% versus 17.9%
Given that dacomitinib does offer the more potent EGFR inhibition, the higher toxicity with the agent was not a huge surprise. Mok pointed out that “the overall total incidence of serious adverse events was similar between the two agents, but the drug-related [serious adverse events] were higher with dacomitinib,” adding that about 10% of patients had to permanently discontinue the drug, versus 7% of patients who had to discontinue gefitinib.
Because of the toxicity, dose reductions had to be used. Dacomitinib had two dose levels, a reduction of of 30 mg/day and another of 15 mg/day, while with gefitinib, there was one dose reduction to 250 mg every 2 days, Mok explained.
“The time to dose reduction was about the same, approximately 3 months, but the median duration of the dose reduction was longer with dacomitinib, at 11.3 months compared with 5.2 months with gefitinib,” he said.
Dacomitinib ultimately emerged as the victor, mainly because of its impressive PFS data, commented John Heymach, MD, chairman of the Department of Thoracic/Head and Neck Medical Oncology at the University of Texas MD Anderson Cancer Center in Houston and a designated ASCO expert. He called the extended median PFS to 14.7 months with the study drug “a really substantial advance … that would clearly put it at the front of the pack in terms of efficacy” — the “pack” being the other targeted therapies available to these patients: gefitinib, erlotinib (Tarceva), and afatinib (Gilotrif).
ALEX: A Knockout
“Chromosomal rearrangements of ALK define a distinct subset of lung cancer patients for whom small-molecule TKIs of ALK are highly effective,” noted Alice T. Shaw, MD, PhD, of Massachusetts General Hospital in Boston. “The current standard of care for patients with newly diagnosed, advanced ALK-positive NSCLC is the first-generation ALK inhibitor, crizotinib.”
But patients invariably relapse on crizotonib, and one of the common and challenging sites of relapse is the CNS, she pointed out. Alectinib is more potent and more brain penetrable than crizotinib and can retain activity against crizotonib-resistant disease, she added.
For this trial, Shaw’s group randomly assigned 303 patients with previously untreated, advanced ALK-positive NSCLC to receive either alectinib (at 600 mg twice daily) or crizotinib (at 250 mg twice daily). ALEX’s primary endpoint was investigator-assessed PFS, and secondary endpoints included ORR, OS, and time to CNS progression.
The results showed, the team reported, that, across the board, alectinib turned in better results than crizotinib:
- 12-month event-free survival rate (investigator-assessed PFS): 68.4% (95% CI 61.0-75.9) versus 48.7% (95% CI 40.4-56.9)
- Event of CNS progression: 12% versus 45% (cause-specific hazard ratio 0.16, 95% CI 0.10-0.28, P<0.001)
- ORR: 82.9% (95% CI 76.0-88.5) versus 75.5% (95% CI 67.8-82.1, P=0.09)
- OS: “Not estimable” for either arm (HR for death 0.76, 95% CI 0.48-1.20)
For PFS, the hazard ratio for disease progression or death was 0.47 (95% CI 0.34-0.65, P<0.001), and the median PFS with alectinib was not reached, the authors stated.
In addition, a follow-up analysis for OS will be performed when approximately 50% of the patients have died, Shaw’s group wrote in the New England Journal of Medicine.
As with dacomitinib, alectinib did stumble a bit when it came to adverse events, which occurred at a higher incidence by five percentage points or more with alectinib versus crizotinib:
- Anemia: 20% versus 5%
- Myalgia: 16% versus 2%
- Increased blood bilirubin: 15% versus 1%
- Increased weight: 10% versus 0%
- Musculoskeletal pain: 7% versus 2%
- Photosensitivity reaction: 5% versus 0%
However, some adverse events that were common with crizotinib were nausea, diarrhea, and vomiting.
“One of the key secondary endpoints was time to CNS progression in the total population,” Shaw stated. “We found that alectinib significantly delayed time to CNS progress compared with crizotinib, with an 84% reduction in the risk of having CNS progression as the first event.”
The results represent a “watershed moment” for the treatment of ALK-mutant NSCLC, Heymach said. “Often, studies comparing similar-type agents will show incremental improvements. This one is different. There is a dramatic difference in efficacy — more than doubling the time to progression or death. It’s also accompanied by improved tolerability.
“Finally, one of the most debilitating things that can occur in these patients with ALK-mutant disease is brain metastasis,” he continued. “What’s really impressive about this study is the dramatic reduction in the risk of brain metastasis — an 84% reduction in the likelihood, which is an absolutely striking result.”
The ARCHER 1050 trial was funded by Pfizer and SFJ Pharmaceuticals Group.