This past week, I saw a new patient who had just moved from another part of the country and needed long-term management of her high risk lung cancer. A never-smoking Asian woman, she was found to have a stage IIIA lung cancer with “N2″ mediastinal lymph nodes involving cancer in her mid-chest. As is typically done, she received chemotherapy with a cisplatin/Alimta (pemetrexed), a very strong treatment option for her lung adenocarcinoma, and she then proceeded to surgery. There, she was found to have a small amount of residual cancer in her mediastinal lymph nodes, which suggests a high risk of recurrence. Her oncologist recommended post-operative radiation to treat this area.
Though radiation to the mid-chest is commonly and I think appropriately favored for patients with residual N2 nodal disease after surgery, especially if they hadn’t received it before surgery, this woman declined the radiation. She was far more receptive to more systemic therapy, especially in the form of targeted therapy once it was discovered that her tumor has a ROS1 rearrangement. This is rare (only about 1-1.5% of lung cancers, disproportionately in younger never-smokers with an adenocarcinoma) and has been found to very often respond well to XALKORI (crizotinib), the same agent used for the 4-5% of patients in the US (more in Asia) who have an ALK rearrangement, for whom XALKORI is approved. XALKORI isn’t technically FDA approved for people with a ROS-1 rearrangement, but it’s often covered by insurers when they are made to understand the profound value of this agent for these rare patients.
But when we talk about XALKORI for patients with an ALK or ROS1 rearrangement, or an EGFR tyrosine kinase inhibitor (TKI) like Tarceva (erlotinib), Iressa (gefitinib), or Gilotrif (afatinib) for those with an EGFR mutation, we’re focusing on the overwhelmingly favorable data obtained in patients with metastatic cancer. It’s an entirely different situation with curable and potentially cured lung cancer. When someone has undergone surgery or chemo/radiation or some other combination for stage I-III NSCLC, we know that some of these people are already going to be cured without adding any other treatment. When we give targeted therapies for lung cancer who may already be cured, we often presume we can only be helping them. However, that wasn’t true when adding Iressa after chemo/radiation for patients with stage III NSCLC — in fact, Iressa was significantly harmful and shortened survival. We decided, with the benefit of hindsight, that this was because the patients on that trial were not molecularly selected as having an EGFR mutation; they didn’t check for or require EGFR mutations, so we presume that 90% didn’t have an EGFR mutation, and we know such patients typically benefit modestly at best from EGFR TKIs. However, when we saw the results of a trial of post-operative (adjuvant) Iressa in early stage NSCLC patients, we saw that not only was there a trend toward worse outcomes for the recipients of Iressa in the overall, molecularly unselected population, but the trend of worse outcomes was especially pronounced in patients with an EGFR mutation. If there was ever an observation that was humbling in highlighting how wrong we could be in our presumptions, it was that one.