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Novel Approaches Explored in HER2-Positive Gastric Cancer

Laura Panjwani
Published: Monday, Jan 18, 2016

Yelena Y. Janjigian, MD

Yelena Y. Janjigian, MD

There is a great need for novel treatments for patients with HER2-positive gastric/gastroesophageal junction (GEJ) adenocarcinomas, a patient population that makes up approximately 30% of those with the disease, says Yelena Y. Janjigian, MD, a medical oncologist at Memorial Sloan Kettering Cancer Center.

The search for novel treatments is even more important considering the recent negative results of the phase III LOGiC trial, which looked at the addition of lapatinib (Tykerb) to capecitabine (Xeloda) and oxaliplatin (Eloxatin) for patients with HER2-amplified gastroesophageal adenocarcinoma.

Median overall survival (OS) in the lapatinib combination arm was 12.2 months (95% CI, 10.6-14.2) versus 10.5 months (95% CI, 9.0-11.3) in the capecitabine and oxaliplatin–only control arm (HR, 0.91; 95% CI, 0.73-1.12). Median progression-free survival (PFS) in the lapatinib and control arms was 6.0 months (95% CI, 5.6-7.0) and 5.4 months (95% CI, 4.4-5.7), respectively (HR, 0.82; 95% CI, 0.68-1.00; P = .0381).

In an interview with OncLive, Janjigian discusses possible causes of the negative LOGiC trial results, HER2 as a driver in esophagogastric cancer, and what the future holds for lapatinib. She also discusses the potential of other treatments for HER2-positive gastric/GEJ cancer, including novel HER2-targeted agents, VEGF inhibitors, and immunotherapies.

OncLive: What did we learn from the phase III LOGiC trial? Is there an understanding as to why lapatinib failed to show a survival benefit?

Janjigian: Based on the trial results, as they stand right now without any additional sequencing data or biomarker results, we clearly do not have a reason why lapatinib failed both in the first- and second-line setting. Based on my experience, I think we need to look at lapatinib as a drug, the trial design, and HER2 as a target in gastric cancer, in order to understand why it failed.

Lapatinib is an oral agent, and certain patients may not have the same levels of the drug built up in their system. Patients who have had gastrectomies, for example, where the drug quickly goes through their system and doesn’t get absorbed, may not benefit from oral drugs, such as lapatinib. Patients who are able to get a full dose of lapatinib without any problems with absorption may have a better benefit.

There are also differences in HER2 expression. HER2 positivity is defined by IHC 2+ and 3+. If IHC 2+, then you perform FISH. Therefore, for patients whose tumors have a high level of HER2 positivity, they may a have a bigger benefit. All of that data needs to be carefully reviewed. Patients who have a high level of HER2 positivity, perhaps IHC 3+ and FISH-positive, may benefit from HER2-directed agents, particularly beyond trastuzumab (Herceptin).

Finally, what it comes down to is that lapatinib may not be sufficient for HER2 inhibition in gastric cancer. We may just need a stronger HER2 inhibitor or HER2 inhibition with other targeted agents or chemotherapy. Gastric cancer is not only HER2 driven, even in HER2 disease.

HER2 amplification by FISH was selected as a biomarker for the LOGiC trial, regardless of HER2 IHC analysis. What questions remain regarding the use of HER2 as a driver for HER2-targeted therapies?

The question everyone asks is, “Would a second study in a population that had high level of HER2 amplification be worthwhile with lapatinib?” I think the answer is, “No.”

We know enough from looking at this disease that lapatinib is probably not going to be sufficient by itself. I wouldn’t subject another 300 patients to chemotherapy plus lapatinib, even in a highly HER2-amplified population. This is because, in my experience and now emerging data suggest, combination therapies are needed. We need to look at combinations of HER2-directed agents, HER2 agents with VEGF inhibitors, and HER2 agents with PD-1 inhibitors.

That is the wave of the future. We’ve got to go forward instead of trying to correct the mistakes we’ve made in trial design and not subject another patient population to a potentially small benefit or a negative trial.

Are any ongoing trials looking at VEGF inhibition in this patient population?

There was a small phase II trial looking at FOLFOX plus bevacizumab (Avastin) and trastuzumab in first-line. That trial, even though there were only data on 35 patients reported, was unprecedented compared to historic control in response rate, OS, and PFS in that patient population.

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