Sequencing treatment in ALK-positive lung cancer
The proverbial question, “what is my best treatment option?” is always on a patient’s mind. With the current treatment options available to us, ALKies, “what should we do?” comes up often. There are all the TKI options (Crizotinib, Ceritinib, Ensartinib, Alectinib, Brigatinib, and Lorlatinib), chemotherapy, radiation therapy and surgery (depending on your stage).
By definition, a first-line therapy is a standard treatment set as the best treatment. If this treatment does not cure the disease or if it causes side effects, other treatments may be added or used. A second line therapy is given after the first-line therapy doesn’t work anymore or has stopped working. The treatment can continue with third line, fourth line, and so on.
The first line treatment can change over time with any cancer. As newer studies find better options, treatment recommendations are modified or changed. Only a decade ago chemotherapy was the standard first-line treatment for all lung cancer (even with ALK because there was no testing done). Only after the discovery of the ALK gene and its linkage to an inhibitor, Crizotinib, in 2011, did the first line treatment for lung cancer patients with an ALK mutation change to Crizotinib. However, there is no hard and fast rule to limit a physician to which medication to use as first line. There’s a “golden standard” but there’s room to deviate. For example, if the standard of care is Lorlatinib but the patient already has high cholesterol levels that cannot be controlled well, a physician may opt to treat the patient with Brigatinib, another FDA-approved first line drug that does not affect cholesterol levels.
Sometimes a patient is limited by their geography as determined by what is currently available to them in their country of residence. For example, Ensartinib is FDA-approved for ALK lung patients in US, but it is usually not chosen because there are other TKIs available (Alectinib, Lorlatinib, or Brigatinib). On the other hand, Ensartinib has been used more widely in China because Ensartinib was used for several clinical trials there and physicians understand it better and are more willing to prescribe it.
From a few research papers, not necessarily in the ALK field or in the lung cancer field, we can glimpse into some preliminary results of medication sequencing and its effects. In breast cancer in 2018, a clinical trial was done to understand the effect of a sequential use of chemotherapy and Trastuzumab (a medicine for HER2 mutations) vs. the combinational use of chemotherapy with Trastuzumab. The result was surprising because the conclusion on more than 280 patients was that the combination therapy did not benefit patients and is not warranted. The researchers followed the patients for more than 5 years and there was no difference in disease-free or overall survival rate between the two cohorts.
For lung cancer, the same question was asked for advanced non-small cell lung cancer patients in China. In the limits of only chemotherapy, radiation therapy and no TKI, the authors found that the combination of chemotherapy with radiation therapy did offer more benefit, though it comes with higher risks of side effects.
Additionally, there was a paper addressing a similar question with combination antibody therapy vs. TKI monotherapy in the realm of EGFR/HER2 lung cancer patients. They had simulated human tumors in a mouse model and found that an antibody combination against EGFR and HER2 was better than monotherapy of a TKI (Erlotinib or Osimertinib) alone.
Should a patient start with the best medication that is available to them? Yes. That is in the definition of first line treatment. “Do I defer it for a different medication?” This is a personal choice and it is the ultimate form of personalized care. Each patient should discuss the various topics important to them and their family to come up with the optimal plan for treatment. Treatment can be different from others because each patient brings in a wide range of variables such as their medical history and their personal preference. Ask lots of questions and don’t be afraid to seek answers to your questions. Empower yourself!
Author: Alice Chou