Fleshing Out HER2-Directed Therapies in GI Malignancies

The field of HER2-positive gastrointestinal (GI) malignancies witnessed a surge of data in 2020 regarding investigational agents, such as the antibody-drug conjugate (ADC) fam-trastuzumab deruxtecan-nxki (Enhertu), that could play a pivotal role in transforming treatment selection in the coming years, said Shubham Pant, MD.

“In spite of COVID-19 [coronavirus disease 2019], many developments and discoveries were made in GI cancers in 2020,” said Pant. “We saw a lot of good early data in phase 1 and 2 trials in the HER2-positive setting. From gastric cancer to cholangiocarcinoma, these newer agents, particularly the HER2-directed ADCs and bispecific antibodies, are really going to change the landscape of HER2-positive GI cancers.”

In an interview with OncLive®, Pant, an associate professor with a joint appointment in the Department of Investigational Cancer Therapeutics and the Department of Gastrointestinal Medical Oncology at The University of Texas MD Anderson Cancer Center, discussed the most exciting updates in GI malignancies, including gastric/gastroesophageal (GEJ) cancer and cholangiocarcinoma from 2020, and spotlighted how HER2 mutations are gaining traction as an actionable target in the space.

OncLive®:How could trastuzumab deruxtecan affect the treatment paradigm of gastric cancer based on the data we’ve seen from the DESTINY-Gastric01 trial?

Pant: Trastuzumab deruxtecan is an interesting therapy that showed good results in HER2-neu–positive patients who had previously been on trastuzumab [Herceptin]. [DESTINY-Gastric01] was a randomized phase 2 trial comparing trastuzumab deruxtecan with chemotherapy in patients with HER2-positive gastric cancer. Interestingly, the median survival [with trastuzumab deruxtecan] was about 12.5 months versus 8.4 months with physician’s choice of chemotherapy. That translates to a hazard ratio of 0.59, which is statistically significant. That is what I found most compelling about the trial.

[Trastuzumab deruxtecan] is going to change the paradigm for these patients. [Moreover,] moving the ADC into the up-front setting is going to change the landscape.

Also, trials were reported in 2020 showing PD-1 inhibitors with chemotherapy and trastuzumab in HER2-neu–positive patients that showed very good response rates. We are looking at these frontline quadruplet combination regimens. Additionally, we are [awaiting] FDA approvals to use these compounds in the clinic in 2021. A number of other HER2-neu targeted agents and small molecules that actually target the HER2-neu mutation [are in the pipeline]. These have up-and-coming, early data.

Do you anticipate that HER2 will emerge as a relevant target in extrahepatic cholangiocarcinoma?

Gallbladder cancer and extrahepatic cholangiocarcinoma are more HER2-neu–positive compared with intrahepatic [cholangiocarcinoma]. We’ve launched the global trial targeting [HER2] with ZW25 [zanidatamab], which is a bispecific antibody. I’m really excited about the prospect of targeting HER2 in these rare malignancies. Just like FGFR fusions came to the floor [in 2020], I am hoping HER2-neu will be the story to be told in the next few years.

We have other genomically targeted agents [under investigation], including [those directed toward] HER2-neu. I am fairly excited about newer targeted agents coming into this field in 2021.

Zanidatamab received breakthrough therapy designation for patients with HER2-positive biliary tract cancer in November 2020. What is unique about that compound?

I’m one of the global leaders on this trial and have experience with [zanidatamab] in the phase 1 setting. Normally, second-line response rates in patients with cholangiocarcinoma are around 5%, as was reported with FOLFOX versus placebo. In our phase 1 expansion trial, although in a small number of patients, zanidatamab [induced] responses close to 50% in this population, which is very exciting.

What is your forecast for 2021 with regard to HER2-directed therapy in GI cancers?

Newer immunotherapies have the potential to change practice. Trastuzumab deruxtecan in patients with HER2-neu gastric cancer who were previously treated with trastuzumab will hopefully move forward in 2021.

In HER2-neu–positive cholangiocarcinoma and gallbladder cancer, we recently launched a global clinical trial of [zanidatamab], trying to look for efficacy in the second-line setting.