Dr. Shaw on Sequencing Strategies in ALK-Positive NSCLC

Alice T. Shaw, MD, PhD, associate professor of medicine at Harvard Medical School, director of Thoracic Oncology and Paula O’Keefe Endowed Chair in Thoracic Oncology at Massachusetts General Hospital, discusses sequencing strategies in ALK-positive non—small cell lung cancer (NSCLC).

The optimal sequencing of ALK inhibitors is still under investigation. However, sequencing strategies could be based on resistance mechanisms, explains Shaw. For example, more than half of patients who progress on a second-generation inhibitor, such as alectinib (Alecensa) or brigatinib (Alunbrig), will have developed a secondary ALK resistance mutation. Because these mutations are still dependent on ALK, another ALK inhibitor could potentially be active against that mutation.

If a patient develops resistance to a second-generation inhibitor, data suggest that lorlatinib (Lorbrena), which was designed to target all of the known ALK resistance mutations, could be very effective. Lorlatinib has been shown to be especially active in patients whose tumors have become resistant due to 1 of these acquired ALK resistance mutations, says Shaw.

For this reason, Shaw recommends sending for repeat biopsy when a patient is failing on a second-generation ALK inhibitor. Tumor biopsies are often done in this setting, but liquid biopsies or circulating tumor DNA analysis could also be very helpful in identifying an underlying ALK resistance mutation. That information may inform the decision to use lorlatinib, or another second-generation inhibitor such as ceritinib (Zykadia) or brigatinib.