Bevacizumab is not FDA approved in gastric cancer, and it is not going to be developed further because there was a large negative AVAGAST study. However, ramucirumab (Cyramza) is a VEGFR2 inhibitor that is FDA approved in gastric cancer. We are opening a trial with Eli Lilly that I am the primary investigator for. It is a Memorial Sloan Kettering Cancer Center trial right now but, if the results look promising, it will become a multicenter trial. In this trial, we are studying ramucirumab with trastuzumab and chemotherapy in the first-line setting.
What about combinations with immunotherapies? Are there any upcoming trials investigating PD-1 inhibition in gastric/GEJ?
We have a trial that will be opening soon and is going through the approval process. It is exploring the possibility that perhaps we should combine PD-1 inhibitors with HER2-directed agents.
We are looking at pembrolizumab (Keytruda) plus trastuzumab and chemotherapy in HER2-positive patients in the frontline setting.
Is there a possibility of PD-1 being used as a single agent in gastric cancer?
There is a large research program to use pembrolizumab as a single agent in pretreated patients in the second- and third-line settings. Across the board, the response rate in unselected patients is probably going to be in a factor of 15% to 20%; that is what the data suggest with nivolumab (Opdivo), pembrolizumab, etc. This is not going to be good enough.
Of course, it is a good place to start if you have a deep and meaningful response in 15% of patients. The responses are going to be more dramatic in hypermutated gastric cancer, where patients have hundreds and hundreds of mutations in their tumor. HER2-positive tumors are not hypermutated, generally. My sense is that PD-1 inhibitors alone will generally not be sufficient in our patients, and we need to capitalize on the HER2 in the tumor and probably do combination therapy.
What potential role could other HER2-targeted agents, besides trastuzumab, have in this space?
In the second-line setting, T-DM1 (Kadcyla) has failed. T-DM1 was positive in patients with breast cancer and everyone was really excited to see the data, but the strategy failed. I think it is because, at the time of trastuzumab resistance in gastric cancer, loss of HER2 and loss of expression on the receptor is a really big problem. T-DM1 still capitalizes on the drug’s ability to bind to HER2.
Therefore, if you don’t have HER2 or if HER2 has been altered, you are unable to strongly bind to the receptor. Thus far, for patients who are still HER2-positive at the time of trastuzumab progression, nothing is currently available.
There might still be a role for T-DM1 in combination. The first step would be to look at it in combination with trastuzumab in the first-line setting.
We are also planning to conduct a large intergroup study investigating paclitaxel plus afatinib (Gilotrif), an irreversible EGFR, HER2, and HER4 inhibitor. EGFR signaling, even though cetuximab (Erbitux) failed in the disease, has potential in at least some population of HER2-positive patients.
I am very interested in studying this in patients with trastuzumab-refractory gastric carcinoma. I have a small, but growing, phase II study of afatinib plus paclitaxel, with a targeted accrual of 46 patients. We have seen some patients with quite dramatic responses. Patients have remained on study for 1 year, so they were long responses. This is not a common occurrence in gastric cancer.
Based on this preliminary data, we are interested in exploring this in the second-line setting, comparing paclitaxel and afatinib with paclitaxel and ramucirumab, which is the standard of care. The idea is to determine if capitalizing on HER2 in the second-line setting is still a viable option because, so far, experience with lapatinib and T-DM1 tells us that perhaps it is not.
My sense is that it is probably not the case. Most experts would agree that part of the reason these trials failed is because they were studying the wrong patient population. HER2 testing is often done on archival samples, which can be 4 years old; you can’t really say that is sufficient. You need to biopsy the patient to determine if they are actually HER2 positive.
Janjigian YY. Lapatinib in gastric cancer: what is the LOGiCal next step? [published online December 23, 2015]. J Clin Oncol. doi: 10.1200/JCO.2015.64.2892.