Bassel El-Rayes, MD: What are the factors that impact my selection of frontline therapy? As we discussed earlier, the molecular profile impacts my selection. With patients who are HER2/neu-positive, I want to use trastuzumab plus chemotherapy in the upfront setting. Patients who are MSI [microsatellite instability]-high, I would consider an immune therapy approach. For patients who have a high CPS [combined positive score] I would consider a combination of immune therapy plus chemotherapy. Therefore, these molecular markers are key in selecting the path of therapy in the upfront setting.
Now the challenge is, unfortunately, that most patients progress, and when that happens we must look at the options available in the second-line setting. We have a number of chemotherapy regimens that have a proven track record in second-line settings. The most commonly used is a combination of a targeted drug called ramucirumab, plus a taxane, usually paclitaxel, or as was done in our case, docetaxel. In randomized trials this combination has shown to be beneficial in the second-line setting.
Other options in the second-line setting could include chemotherapy alone, such as a taxane or irinotecan. You could potentially use ramucirumab alone, which has shown to be beneficial in a randomized phase 3 trial as a single agent in the second-line setting.
So there are many treatment options for the second-line setting, and the choice in the front-line setting impacts the choice in the second-line setting. Of course, if you’re using FOLFOX [folinic acid, fluorouracil, oxaliplatin], you want to move over to a different regimen in the second-line setting.
The other things that can impact your choice in the second-line setting include patients’ performance status, organ function, as well as toxicities from the frontline setting that linger into the second-line setting, specifically neuropathy.
However, when patients progress in the second-line setting, what are the options in the third-line setting? In the third-line setting there are a number of options, and those are driven by the choice of agents used in the first-line and second-line settings, as well as the molecular profile of the patient.
Let’s start with the patients who are HER2/neu-negative. In the third-line setting, you are usually using another chemotherapy approach. Some of the agents that have shown activity in the third-line setting include a drug called TAS-102 [trifluridine, tipiracil], which is an oral agent that has shown benefit in a randomized trial.
Additional chemotherapy agents used in the third-line setting are agents like irinotecan, which have been used in smaller trials. If you haven’t used any of those agents in the frontline or second-line setting, you could potentially use them in the third-line setting.
Patients who have not been exposed to immune therapy in the frontline and second-line setting could potentially get immune therapy in the third-line setting, and we have data to show that approach has activity in that setting as well.
Transcript edited for clarity.
Case: A 66-Year Old Male With HER2+ Gastric Cancer