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New generations of potent ALK inhibitors have been designed with extensive CNS activity and the ability to overcome acquired resistance mutations.
Sai-Hong Ignatius Ou, MD, PhD
The approval of crizotinib was a paradigm-altering advance for patients with ALK-positive non-small cell lung cancer (NSCLC). Across two large phase III trials, treatment with the ALK inhibitor demonstrated roughly a 50% improvement in progression-free survival (PFS) compared with various chemotherapy regimens.
Despite this impressive activity, crizotinib has been shown to have limited activity in patients with brain metastases. In addition, secondary resistance mutations often render the agent ineffective.
To address these concerns, new generations of potent ALK inhibitors have been designed with extensive CNS activity and the ability to overcome acquired resistance mutations, such as L1196M. The two leading second-generation inhibitors include ceritinib (Zykadia) and alectinib, according to Sai-Hong Ignatius Ou, MD, PhD, during his presentation at the 15th Annual International Lung Cancer Congress.
"Crizotinib has some limited activity in brain metastases, and we all have anecdotal evidence that brain metastases are one of the major pathways for failure on crizotinib," Ou, a health science associate clinical professor at the University of California, Irvine, said during his presentation. "If you make it to a second-generation ALK inhibitor trial, about 49% of patients have brain metastases. It's important to look at the percentage of patients with brain metastases. As we go further along with the treatment, it's becoming a major, major problem."
In July 2014, alectinib gained its first approval as a treatment for patients in Japan. Additionally, the drug received an FDA breakthrough therapy designation in 2013.
In the phase II portion of the single-arm AF-001JP study, 46 crizotinib-naive patients received treatment with alectinib at 300 mg twice daily.1 The overall response rate (ORR) was 93.5% (95% CI, 82.1-98.6%) and the 12-month PFS rate was 83%. Of the 14 patients with CNS metastases at baseline, 64% remained progression-free after 12 months of treatment.
The only major grade 3 adverse event was neutrophil count decrease, which occurred in 7% of patients. The most common all-grade adverse events were dysgeusia (36%), rash (33%), elevated AST (33%), elevated blood bilirubin (33%), constipation (29%), and elevated blood creatinine levels (29%).
The phase III ALEX study is comparing alectinib with crizotinib in untreated patients with ALK-positive NSCLC. In this study, alectinib will be administered at 600 mg twice daily, with food. The study hopes to enroll 286 patients, with early results expected in 2018.
The FDA approved ceritinib following progression on crizotinib for patients with ALK-positive NSCLC in April 2014. Prior to the approval, the drug received a breakthrough therapy designation, priority review, and orphan product designation.
In the phase I ASCEND-1 trial, 246 patients with ALK-positive NSCLC received treatment with ceritinib at 750 mg daily.2 Both crizotinib-naive and pretreated patients were enrolled in the trial. For the total population, the ORR was 58.5%. The ORR was 66.3% in ALK inhibitor naive patients (n = 83) and 54.5% in pretreated patients (n = 163).
Ceritinib demonstrated similar activity in patients with baseline brain metastases. The ORR was 50% in treated patients (n = 98) and 69.2% in crizotinib-naive patients (n = 26). The duration of response had not been reached for crizotinib-naive patients with brain metastases.
The most common all-grade side effects in the ASCEND-1 trial were diarrhea (86%), hemoglobin decrease (84%), ALT increase (80%), nausea (80%), AST increase (75%), and vomiting (60%). The most common grade 3/4 adverse events were ALT increase (27%), AST increase (13%), and glucose increase (13%). Overall, 59% of patients required at least 1 dose reduction during the trial.
"There's an interest in doing snack trials—that somehow a small amount of food might help the toxicity. At least in my experience, [ceritinib] seems to be the most toxic of all the first and second agents," lung cancer expert Corey J. Langer, MD, from the University of Pennsylvania, said during a question and answer session at the congress.
AP26113 was one of the earlier next-generation ALK inhibitors to enter clinical trials, but suffered an early challenge with toxicity. In a phase I/II study, the ORR with AP26113 was 69% in crizotinib resistant patients (n = 51) and 83% of treatment-naive patients experienced a response.3 The ORR was 69% for patients with brain metastases (n = 13).
However, in the study, early onset pulmonary symptoms were observed in 10% of patients, particularly at the 180 mg or higher daily dose. To further explore an optimal dose, the phase II ALTA trial was opened in April 2014. This study will administer AP26113 at 90 mg daily followed by either 180 or 90 mg. The primary endpoint is ORR.
"The randomized phase II trial involves two different doses because a few patients had pulmonary toxicity. This study will look at the 180 vs 90 mg once a day dose," Ou said.
While the second-generation agents appear effective in patients with CNS metastases, most of these therapies have limited efficacy against the solvent-front (ie, the solvent-exposed region of the kinase domain) mutation G1202R.
One second-generation agent, manufactured by Pfizer, builds upon the molecular structure of crizotinib. This agent, PF-06463922, is currently being explored in a phase I/II study specifically in patients with ALK and ROS1 mutations. Given its molecular structure, PF-06463922 could demonstrate activity in patients with G1202R mutations, Ou believes. Further research is still needed to gain a definitive answer.