Trial Shows Strong Response to Lorlatinib in NSCLC Patients

ALK-positive and ROS1-positive patients benefit

The next-generation tyrosine kinase inhibitor lorlatinib (Pfizer Inc.) led to overall response rates ranging from 33% to 90% in cohorts of patients with ALK-positive and ROS1-positive advanced non–small-cell lung cancer (NSCLC), including heavily pretreated participants, in a phase 2 trial. Side effects were generally manageable and primarily mild to moderate, Pfizer said.

The trial results were presented by Professor Benjamin Solomon, lead investigator and medical oncologist at Peter MacCallum Cancer Centre in Melbourne, Australia, at the International Association for the Study of Lung Cancer 18th World Conference on Lung Cancer in Yokohama, Japan.

 “These are comprehensive data in non–small-cell lung cancer patients previously treated with second-generation ALK inhibitors who currently have few available treatment options,” Solomon said. “Controlling brain metastases is very important to these patients and an especially challenging aspect of treating this disease. We saw excellent intracranial responses in all patient groups, including those who were heavily pretreated.”

 Crizotinib (Xalkori, Pfizer) was the first drug approved for patients with ALK-positive and ROS1-positive NSCLC. By understanding the mutations that occurred in patients that rendered their tumors resistant to crizotinib and other ALK inhibitors, Pfizer said, it was able to design a molecule with the potential to overcome that resistance and inhibit ALK despite these mutations.

The phase 2 study examined the antitumor activity and safety of lorlatinib in 275 patients with or without asymptomatic, untreated, or treated brain metastases. Patients were enrolled in six cohorts based on biomarker (ALK-positive or ROS1-positive) and prior therapy. The primary endpoints were objective response rate (ORR) and intracranial ORR (IC-ORR) confirmed by independent central review. Results by clinically relevant groups showed:

  • ALK-positive treatment-naïve: ORR, 90% (27/30; 95% confidence interval [CI], 74–98); IC-ORR, 75% (6/8; 95% CI, 35–97)
  • ALK-positive previously treated with crizotinib with or without chemotherapy: ORR, 69% (41/59; 95% CI, 56–81); IC-ORR, 68% (25/37; 95% CI, 50–82)
  • ALK-positive previously treated with a non-crizotinib ALK inhibitor with or without chemotherapy: ORR, 33% (9/27; 95% CI, 16–54); IC-ORR, 42% (5/12; 95% CI, 15–72)
  • ALK-positive previously treated with two or three prior ALK inhibitors with or without chemotherapy: ORR, 39% (43/111; 95% CI, 30–49); IC-ORR 48% (40/83; 95% CI, 37–59)
  • ROS1-positive regardless of prior treatment: ORR, 36% (17/47; 95% CI, 23–52); IC-ORR, 56% (14/25; 95% CI, 35–76)

Lorlatinib was generally tolerable. Most adverse events were mild to moderate and were managed by dose reductions or delay or with standard medical therapy. There were no treatment-related deaths and a low (3%) rate of discontinuation due to drug-related adverse events.

In April 2017, the FDA granted a breakthrough therapy designation for lorlatinib for the treatment of patients with ALK-positive metastatic NSCLC previously treated with one or more ALK inhibitors.

Lung cancer is the leading cause of cancer death worldwide. NSCLC accounts for about 85% of lung cancer cases and remains difficult to treat, particularly in the metastatic setting. Approximately 75% of NSCLC patients are diagnosed late with metastatic or advanced disease where the five-year survival rate is only 5%.

Source: Pfizer; October 16, 2017.