Alecensa Could Become New First-Line Standard in Subset of Patients With Lung Cancer

Patients with advanced or recurrent ALK-positive non—small cell lung cancer (NSCLC) being treated with Alecensa (alectinib), a second-generation oral ALK-targeting agent, had 66 percent higher progression-free survival (PFS) rates than those being treated with Xalkori (crizotinib), the current standard. This finding comes from a prespecified interim analysis of an open-label phase 3 Japanese study presented at Annual Meeting of the American Society of Clinical Oncology (ASCO), a gathering of 30,000 oncology professionals in Chicago.

The median PFS had not yet been reached at the time of data analysis in the arm receiving Alecensa, said lead study author Hiroshi Nokihara, in presenting the data.

“Based on these results, we believe that Alecensa is the new standard first-line therapy for ALK-positive NSCLC,” said Nokihara of the National Cancer Center Hospital in Tokyo, Japan.

Alecensa, a potent ALK inhibitor with activity in the central nervous system (CNS), was granted accelerated approval by the FDA in December 2015 for the treatment of patients with ALK-positive NSCLC who have progressed on or are intolerant to Xalkori, which is the current standard frontline treatment for ALK-positive NSCLC.

PFS with Xalkori in this patient population is approximately 11 months, Nokihara said. “All patients eventually relapse on Xalkori, mainly due to secondary ALK mutations, ALK amplification, or CNS metastases,” he said.

A previous Japanese phase 1/2 study established the early efficacy of Alecensa in ALK inhibitor-naïve patients, with a median PFS that surpassed 29 months.

In the phase 3 J-ALEX study, 207 Japanese patients with ALK-positive advanced or recurrent NSCLC who had not been previously treated with an ALK inhibitor were randomized to Alecensa, 300 mg twice daily, or Xalkori, 250 mg twice daily. Treatment was continued until disease progression or unacceptable toxicity.

Baseline characteristics were well balanced between the groups, with the exception that a higher proportion of patients randomized to Xalkori had brain metastases by independent review compared with those randomized to Alecensa (27.9 percent vs 13.6 percent, respectively).

More than 90 percent of the patients were positive for ALK by immunohistochemistry and fluorescence in situ hybridization while the status of the remaining participants was confirmed with reverse transcription polymerase chain reaction testing. About one-third of patients in each arm had received one line of chemotherapy before entry. The duration of follow-up was 12.0 months in the Alecensa arm and 12.2 months in the Xalkori arm.

Grade 3-4 adverse events (AEs) occurred with greater frequency in the Xalkori arm compared with the Alecensa arm (51.9 percent vs 26.2 percent, respectively). Discontinuation of study drug due to AEs occurred more frequently in the Xalkori arm compared with the Alecensa arm (20.2 percent vs 8.7 percent, respectively), as did dose interruption due to AEs (74.0 percent vs 29.1 percent, respectively).

Constipation was the most common all-grade AE in the Alecensa group (35.0 percent), followed by nasopharyngitis (20.4 percent), dysgeusia (18.4 percent), nausea (10.7 percent), aspartate aminotransferase (AST) increase (10.7 percent). In the Xalkori group, the most common adverse events were nausea (74.0 percent), diarrhea (73.1 percent), vomiting (57.5 percent), visual disturbance (54.8 percent), dysgeusia (51.9 percent), constipation (44.2 percent), and elevations in alanine aminotransferase (31.7 percent), and AST (30.8 percent). Eight patients in each arm withdrew from the study due to interstitial lung disease. In the Xalkori arm, five patients discontinued due to impaired hepatic function and four discontinued following an increase in alanine aminotransferase level.

Objective response rates (ORRs) as determined by investigators were 85.4 percent in the Alecensa group and 70.2 percent in the Xalkori group. As assessed by independent review, ORR was 91.6 percent in the Alecensa arm, which was consistent with the phase 1/2 data, and 78.9 percent in the Xalkori arm.

The primary endpoint, median PFS as assessed by independent review, was significantly improved with Alecensa. Median PFS not reached in the Alecensa arm, with a lower confidence interval of 20.3 months, compared with a median PFS of 10.2 months in the Xalkori arm. In the subgroup of patients with brain metastases at baseline, the hazard ratio for the primary endpoint with Alecensa versus Xalkori was 0.08.

“This was not a purely frontline study in that some of the patients had received one prior line of chemotherapy,” said invited discussant Shirish M. Gadgeel, a professor at the Karmanos Cancer Institute at Wayne State University, Detroit.

Gadgeel gave a cautious “yes” in answering the question of whether Alecensa should be the new standard frontline therapy in this setting. The 0.34 hazard ratio and the superior toxicity profile with Alecensa are compelling, he said, but “there’s clearly a note of caution in that these results are based on an interim analysis, though planned, and we still await the results of the global ALEX study, and certain that some, if not many, might have reluctance in considering such a switch at this point.”