CTA: Are some agents more likely to have efficacy in crizotinib-naive ROS1-positive NSCLC?

Dr Shaw: The best-established agent for TKI-naive ROS1-positive NSCLC is crizotinib. Ceritinib has also been shown in a Korean study to have antitumor activity in TKI-naive ROS1-positive NSCLC.2


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Yet ceritinib has more toxicity than crizotinib, so I would consider crizotinib the standard first-line agent for ROS1-positive NSCLC.

CTA: Do you believe the brain-penetrant attributes of the next generation of ALK/ROS1 TKIs (such as lorlatinib, in the data presented at ASCO 2017) will continue to result in the most durable overall responses for patients with brain metastases?

Dr Shaw: Yes, a proportion of ROS1-positive NSCLC patients do have (or will develop) CNS metastases, and in these patients, CNS-penetrable agents are very important.

Extrapolating from the ALK field, I would anticipate that CNS-penetrable ROS1 inhibitors will be able to control and prevent CNS metastases much more effectively than crizotinib.

CTA: What is the main focus of ongoing research?

Dr Shaw: The main focus of ongoing research is defining mechanisms of resistance causing relapses on crizotinib.

About one-half of patients develop an on-target resistance mutation, with the solvent front mutation ROS1 G2032R predominating. These tumors may still be ROS1-dependent, and may respond to next generation ROS1 agents with G2032R activity (like TPX-0005).

The remaining one-half of patients do not, however, have ROS1-resistance mutations, and their tumors may no longer be ROS1-dependent (instead driven by bypass or alternative signaling pathways). For these patients, combination strategies may be most effective.

Current research is focused on identifying these bypass tracks and developing rational therapeutic combinations.

Finally, an active area of ongoing research focuses on the minimal residual disease state and characterizing drug-tolerant cancer cells (ie, persisters) that eventually give rise to full-fledged resistant cells. 

References

  1. Dagogo-Jack I, Shaw AT. Expanding the roster of ROS1 inhibitors. J Clin Oncol. 2017 May 18. doi: 10.1200/JCO.2017.73.2586 [Epub ahead of print]
  2. Lim SM, Kim HR, Lee JS, et al. Open-label, multicenter, phase II study of ceritinib in patients with non–small cell lung cancer harboring ROS1 rearrangement. J Clin Oncol. 2017 May 18. doi: 10.1200/JCO.2016.71.3701 [Epub ahead of print]