Higher Dose Trastuzumab Shows No Significant Impact on Survival in Gastric Cancer

Manish Shah, MD

While the ToGA study showed a survival benefit with trastuzumab (Herceptin) plus chemotherapy in HER2-positive gastric cancer, the drug proved no more efficacious when given in larger doses, according to Manish Shah, MD.

The drug was studied in the phase III Heloise study, which compared the efficacy and safety of two dosing regimens consisting of trastuzumab with cisplatin plus capecitabine chemotherapy in patients with gastric cancer. Patients were randomized to receive chemotherapy with either an 8 mg/kg loading dose of trastuzumab followed by 10 mg/kg of the agent every 3 weeks or an 8 mg/kg loading dose of trastuzumab followed by 6 mg/kg every 3 weeks.

The study was prompted by patients who were thought to be underdosed in the ToGA study, which initially examined the combination, says Shah.

In an interview with Targeted Oncology, Shah, Bartlett Family Associate Professor of Medicine, director, Gastrointestinal Oncology Program, Weill Cornell Medical College, discusses the impacts the Heloise study had on the oncology community.

TARGETED ONCOLOGY:Can you tell us about the Heloise study?Shah:The Heloise study is a phase III study that was performed to evaluate the dose of trastuzumab in gastric cancer. As you're aware, the ToGA study was the first study that evaluated trastuzumab in HER2-positive gastric cancer, and it did demonstrate a survival advantage. Since that time, trastuzumab, has been approved for the first-line treatment of HER2-positive gastric cancer.

What we found in the Heloise was very interesting. About one-third of patients seemed to be underdosed. When we checked the trough levels of their drug, it was very, very low, or below what we'd expect from patients with breast cancer. This group, the ones that had the low trough levels of the drug, seemed to have a worse survival. They seemed to be enriched in patients who had a large tumor burden. So they had their primary tumors in place, they had a marginal performance status, and they had visceral organ involvement.

The Heloise study was performed in this population, which was a high-risk population, to see if a high dose of trastuzumab could improve outcomes in these patients. It was a challenging study to enroll, because we were looking for performance status 2 patients who had their primary tumors in place, who had visceral metastases, and who were good candidates to receive cisplatin. The chemotherapy was high-dose cisplatin and standard Xeloda with trastuzumab standard dose, and the standard dose is an 8 mg/kg bolus, and then a 6 mg/kg every 3 weeks. The experimental arm was the same chemotherapy plus the high dose trastuzumab, and the high dose there was still the 8 mg bolus, and then a 10 mg/kg maintenance.

What we found was with the higher dose of trastuzumab, we were able to get increasing levels of trastuzumab trough levels. So there was a significant difference there. High doses of trastuzumab do increase your trastuzumab concentration, and we found that that can be done safely, so we didn't see any new safety events. Interestingly, even with the high dose, we didn't see any cardiac toxicity either.

Unfortunately we did not see an improvement in survival in these patients. The patients who received the high dose arm had the same survival as patients who received the standard dose arm. In that respect it was a negative study, but it did provide important safety signals and it established the standard dose of trastuzumab for gastric cancer. So the ToGA study is the standard dose and schedule, and that's what we should continue on.

I think from that standpoint it's a very important study.

TARGETED ONCOLOGY:Do you think there will be any next steps since it didn't demonstrate a better survival?Shah:Trastuzumab has been available for a long time, certainly in the breast cancer space and then in gastric cancer for the last few years. It's not clear if modifying the dose of trastuzumab is going to actually improve outcomes at this point, so I think the field is moving toward newer HER2 targeting agents, such as pertuzumab as a first-line study with trastuzumab in gastric cancer. That's called the JACOB study, and there was another other study involving TDM1, which is a HER2 drug antibody conjugate, that was evaluated in the second line setting in gastric cancer. Those results were actually presented a few months ago and were also unfortunately negative.

TARGETED ONCOLOGY:Would combining trastuzumab with any other agents in this space make sense?Shah:The other drugs that have been targeting trastuzumab that have not had positive results include the oral tyrosine kinase inhibitor lapatinib, which is a HER1 and HER2 inhibitor. There is some very nice preliminary data from one of the hospitals that looks at afatinib, which is a HER1 and HER2 targeting agent. There does seem to be some preliminary activity there but it's not there yet. it's not clear yet if trastuzumab plus that drug is going to be better or not.

There is some data looking at trastuzumab plus antiangiogenic therapy such as bevacizumab, and that is very promising as well. That might be another thing to target for the HER2 positive patients.