Alan P. Venook, MD: It’s always the challenge in oncology to determine who can tolerate treatment. Some of that is in the eyes of the beholder, and some of that is what the patient wants. Patients with gastric cancer often are quite beat up. Certainly, if they presented with advanced disease in the first place, maybe they were malnourished, then they got chemotherapy for 4 or 6 months, they may not be in very good shape for subsequent treatment. Although in our hands, probably 8 out of 10 patients are candidates for subsequent treatment. It’s a matter of the performance status and, realistically, whether you think you can get treatment into them without doing more harm than good.

In my experience, patients who’ve had their primaries resected are patients likely to go on to receive subsequent-line therapy. Patients who present with advanced disease may not be in a condition to do so. That’s an oncologist’s judgment that makes a decision there.

Yelena Y. Janjigian, MD: In terms of second-line therapy, the majority of our patients who are fit and have good functional status go on to receive second-line therapy. Historically, paclitaxel or irinotecan-based therapies have been the backbone for second-line therapy, and now we have plenty of data to highlight the importance of VEGFR2 inhibition in metastatic gastric cancer. Ramucirumab is FDA approved for use in second-line therapy, either monotherapy or in combination with paclitaxel. The majority of our patients who are fit have symptomatic disease, and therefore a combination therapy is appropriate for these patients. Therefore, for the majority of our patients with HER2-negative disease, we treat them with paclitaxel and ramucirumab, which is the standard of care in the second-line setting.

The question remains of what to do with the HER2-positive patients in second-line setting. Well, important data highlight that the loss of HER2 can occur beyond trastuzumab progression. For these particular patients, if one is to consider HER2-targeted agents in second-line setting, the importance of reassessment of HER2 needs to be considered on second biopsy because up to 20% of these tumors lose HER2 expression at the time of trastuzumab resistance.

With that being said, there has not been a single trial to validate use of other HER2-targeted agents beyond trastuzumab in second-line setting. Unfortunately, TDM1 trials failed. Lapatinib failed in the second line, likely due to patient selection, the heterogeneity of this tumor, and dependence on other signaling pathways beyond HER2 in the second line. Therefore, with the advent of immunotherapy and anti—PD-1 agents, the second and third-line therapy options have expanded and have become more exciting in the last year.

Alan P. Venook, MD: There are many challenges to treating patients with advanced gastric cancer, especially beyond the first line. One, of course, is whether they can tolerate the treatment, especially their malnourished status, which is commonly a problem. There are treatments that are approved in subsequent lines, ramucirumab and paclitaxel, for example. They have modest efficacy. They’re probably of some value, but you have to use them cautiously because patients may not tolerate subsequent-line treatment. Especially if they’ve had a platinum upfront, they may be prone to neuropathy with the paclitaxel.

First of all, can you treat them? Are there any targeted therapies worth using? Well, it’s hard to say. There have been studies looking at Herceptin, although it’s trastuzumab, that would more be a first-line treatment. For subsequent-line treatment, there are studies that have really failed to show a lot of benefit to subsequent treatments. Interestingly there are a few studies in gastric cancer with the checkpoint inhibitors have been plus or minus. A study just came out the other day that was negative, that didn’t show a positive effect in the checkpoint inhibitors. So, I think it’s not so much the choice of treatment as it is how much durability you get and how willing patients are to be treated. My experience is that once you’re into this disease for a year or so, for many patients, they can’t withstand treatment.

Zev A. Wainberg, MD: Immunotherapy, which has now been proven in gastric cancer as having a role, fills an unmet need in this disease in many ways. First of all, we recognize that there is going to be a subgroup of patients with gastric and gastroesophageal junction adenocarcinoma whose tumors can be immuno-sensitive. And the first demonstration of that is obviously with the checkpoint inhibitors. But it goes beyond that. There are other ways in which we can try to use the immune system to attack these malignancies. When one looks at gastric and GEJ cancers as opposed to some of the other GI cancers, this is a more immuno-sensitive cancer setting. So, we’re hopeful that this does fit an unmet need. We need more therapies in this disease, generally speaking, and right now a lot of the drug development emphasis is on immunotherapy. Whether it will be by itself or with combinations, that part we don’t know yet, but we expect the next few years to figure that out.

Transcript Edited for Clarity