Transcript: Johanna C. Bendell, MD: David, we’ve seen a couple of trials that have looked at continuation of trastuzumab into the second-line setting. Tell us what they’ve shown but also what they’ve told us about the biology of HER2-positive gastric cancer?

David H. Ilson, MD, PhD: I think the current guidelines for use of HER2-targeted agents are pretty clear. For HER2-positive patients, trastuzumab should be included as part of first-line chemotherapy. Unfortunately, first-line screening of pertuzumab didn’t add to trastuzumab. Also, the first-line combination with lapatinib, a tyrosine kinase inhibitor [TKI], didn’t add benefit. But there are important studies in the second line that have defined the standard of care. There was a very important randomized phase II trial from Japan. It was a small study, but it looked at patients in the second line who had progressed on frontline chemotherapy plus trastuzumab, and there was neither a survival nor a progression-free survival benefit for continuing trastuzumab into second-line treatment. Those are probably the best data that we have. No signal.

The other signal comes from the T-DM1 [ado-trastuzumab emtansine] study, because T-DM1 [ado-trastuzumab emtansine], arguably, is a better drug than trastuzumab. But when T-DM1 [ado-trastuzumab emtansine], which is a conjugate of the microtubule agent plus a trastuzumab-like antibody, was compared head-to-head with paclitaxel or docetaxel second-line chemotherapy, there was no advantage. I think those 2 data sets indicate that continuing a trastuzumab-like molecule into second-line therapy does not convey a benefit.

Standard practice really should be to stop the drug, not continue it into second-line treatment. What’s the biologic explanation? Why do patients become resistant to trastuzumab? Why don’t they respond to other agents? It is clear, if you actually rebiopsy patients, up to 15% to 20% may actually lose their HER2 expression. That’s a potential mechanism of resistance.

There also are a number of pathways that are affected and amplified and acquired, including EGFR amplification, MET amplification, acquisition of certain mutations in the PI3 kinase, PTEN pathway that may mitigate HER2 resistance. All those pathways provide hypotheses to test ways to potentially overcome resistance in the second-line setting. Should we rebiopsy patients? I think we would rebiopsy patients on a trial. I think if you want to put a patient on a committed second-line HER2-targeted trial, you want to know whether or not they lost their HER2 expression. And that can be, from our experience from Memorial Sloan Kettering Cancer Center, about 15% of the time.

Johanna C. Bendell, MD: Kohei, you’ve done a lot of work with HER2-positive patients. HER2-positivity is higher in Japan. Tell us a bit about some emerging therapies that we might have with HER2-positive disease and your approach there.

Kohei Shitara, MD: As mentioned by David, there are some important data regarding what the resistance mechanism of trastuzumab is. One is the very important heterogeneity in gastric cancer and HER2 expression and activation of the downstream or other growth factor pathways. One very important new agent is trastuzumab deruxtecan [DS-8201a], an antibody drug conjugate compound using the DNA topoisomerase inhibitor. This compound is efficient and has a higher drug-to-antibody ratio compared with T-DM1 [ado-trastuzumab emtansine]. So there are many agents for 1 drug. An interesting characteristic as the DNA topoisomerase inhibitor has an EPR [enhanced permeability and retention] effect. Released, this payload also attacks the HER2-negative tumor or HER2-negative cells. This is called the bystander effect. Studies suggest better activity of this compound compared with T-DM1 [ado-trastuzumab emtansine], especially in HER2-low expressed tumors.

We conducted a first-in-human study and expanded on it. Even in gastric cancer, we observed a 44% objective response rate with a median PFS [progression-free survival] of 5.6 months, even for the very heavily pretreated patient population. I think this is still not a perfect result, but I think this agent is clearly active. And currently, we are doing a randomized phase II trial to compare this DS-8201a and chemotherapy. We finished the enrollment and will hopefully have data in the future.

And another therapy is a Fc-modified HER2 antibody with high ADCC [antibody dependent cell-mediated toxicity] activity. This compound shows there is single-agent activity for HER2-positive trastuzumab-resistant breast cancer and gastric cancer. A recent press release suggests that there are positive results from a phase III trial in breast cancer that showed improved outcomes compared with standard chemotherapy after several lines of treatment. In gastric cancer, the combination with pembrolizumab showed promising activity in the HER2-positive as well as PD-L1 [programmed death-ligand 1]—positive patient population. So I think this warrants further investigation.

Transcript Edited for Clarity