Pfizer’s son of Xalkori impresses in phase 2 NSCLC trial

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The trial linked lorlatinib to an intracranial ORR of 48% in heavily pretreated NSCLC patients

Pfizer has posted a full look at data from a phase 2 trial of lorlatinib in patients with advanced non-small cell lung cancer (NSCLC). The ALK inhibitor triggered responses in a significant minority of heavily pretreated patients, suggesting it can play a role in NSCLC treatment pathways.

Investigators enrolled 275 ALK or ROS1-positive NSCLC patients with or without asymptomatic, untreated or treated brain metastases. The patients had undergone varying degrees of treatment before joining the study. Once in the trial, they received 100mg of lorlatinib once a day. 

In the 111 ALK-positive patients who had undergone treatment with two or three ALK inhibitors and, in some cases, chemotherapy, lorlatinib achieved an objective response rate (ORR) of 39%. The intracranial ORR among the 83 patients in this group with brain metastases was 48%.

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Those ORRs in heavily pretreated patients have raised hopes that lorlatinib will emerge as an option for those who progress following treatment with existing ALK inhibitors, such as Pfizer’s own Xalkori.  

That is one part of the path Pfizer envisages for lorlatinib, the discovery of which grew out of its experience of treating patients with Xalkori. 

“By understanding the mutations that occurred in patients that rendered their tumors resistant to Xalkori and other ALK inhibitors, medicinal chemists working at Pfizer were able to design a molecule with the potential to overcome that resistance and inhibit ALK despite these mutations,” Mace Rothenberg, M.D., chief development officer, oncology at Pfizer said in a statement. 

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Lorlatinib was particularly effective in patients who had previously received Xalkori, either with or without chemotherapy. In this population, lorlatinib recorded an ORR of 69% and intracranial ORR of 68%. Those figures far exceed the ORRs achieved in patients who received other ALK inhibitors. The ORR and intracranial ORR in those groups came in at 33% and 42%, respectively.  

The other ALK inhibitors—Novartis’ Zykadia, Roche’s Alecensa and Takeda’s Alunbrig—came to market after Xalkori and originally fought over patients whose tumors had developed resistance to Pfizer’s pioneering product. That began to change when Novartis picked up a first-line approval for Zykadia earlier this year.

As such, while part of Pfizer’s plan is to show lorlatinib is better than the competition at inhibiting the ALK mutations that drive tumor resistance to Xalkori, the drug’s first-line performance is also a factor. The ORR and intracranial ORR in these populations came in at 90% and 75%, respectively. 

Pfizer, which picked up a breakthrough tag for lorlatinib in April, plans to discuss the data with the FDA and other regulators. 

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