Overlap Between HER2 and PD-L1 Expression in Trastuzumab-Refractory Gastric Cancer or GEJ Adenocarcinoma

Yelena Janjigian, MD, Memorial Sloan Kettering Cancer Center, New York, NY, discusses findings from a preliminary biomarker analysis of the DESTINY-Gastric03 trial, which explored concordance between local and central HER2 testing and overlap of PD-L1 and HER2 expression in gastric cancer/gastroesophageal junction (GEJ) adenocarcinoma. The DESTINY-Gastric03 trial is an ongoing phase 1b/2 study of trastuzumab deruxtecan in this patient population.

The findings from the biomarker analysis were presented at the 2022 ESMO World Congress on Gastrointestinal Cancer in Barcelona, Spain.

Transcript:

My name is Dr. Yelena Janjigian. I'm a medical oncologist and chief of GI Oncology Service at Memorial Sloan Kettering Cancer Center in New York City. It's such a pleasure to be here at the world ESMO GI Congress in Barcelona. We're in person discussing data from the DESTINY-Gastric03 preliminary biomarker analysis.

DESTINY-Gastric03 is a trial looking at the antibody drug conjugate trastuzumab deruxtecan (T-DXd) in combination with chemotherapy and immunotherapy. As you know, T-DXd is an important drug for HER2-positive gastric cancer. We have data supporting the use of trastuzumab deruxtecan in second-line treatment, after trastuzumab progression, and in third-line treatment, in the US, Europe, and Japan.

Our DESTINY-Gastric03 study analyzed the combination of 5-FU or capecitabine in combination with trastuzumab deruxtecan and in combination with anti-PD-1 agents such as durvalumab or pembrolizumab.

DESTINY-Gastric03 is a large study accruing patients over 70 sites, and we have over 200 patients accrued. If you have the study open near you, please consider helping us with accrual.

At today's Congress, we presented the initial biomarker analysis in the first 44 patients that had samples available for analysis. The most important part we wanted to explore is whether there is high degree of concordance between HER2 overexpression tested centrally at the study center or locally at the institutions that were enrolling the patients. We did not mandate central confirmation for the biomarkers before the patients were enrolled, and patients were selected based on the HER2 overexpression by IHC 3+ or IHC 2+ FISH positivity done locally.

In this population, both previously untreated first-line patients and second- and third-line patients with heavily pretreated disease were included. Once we received the tissue slides, we then did immunohistochemistry testing for HER2 using the Dako HercepTest and for 22C3 PD-L1 combined positivity score. We also tested the tumors using NGS platform by FoundationOne.

Our most important finding is that 80% of the testing showed concordance between HER2 testing centrally and locally. In 20% of cases, the testing was discordant, and that occurred mostly in patients with IHC 2+ or FISH-positive tumors, where then subsequent testing locally revealed that those tumors were actually HER2-negative.

This is a critical finding for two reasons. One is that it highlights the importance of HER2 testing done centrally for prospective phase 3 studies. Second, we know from previous data that the patients with variable testing, in other words discordant testing, tend to not do as well on treatment with HER2 inhibition. They don't benefit as much. This is therefore an important factor for biomarker selection in clinical trials.

We then tested the tumors for PD-L1, and we found that the majority, 85%, of patients had high PD-L1 CPS overexpression of CPS 1 or greater. We also found that a high proportion of patients had CPS 5 or greater. This is not a surprise. It's a confirmatory finding. We have also previously seen that a high level of HER2-positive tumors are also PD-L1 overexpressing in the KEYNOTE-811 study.

That's great because we understand that patients can tolerate the combination of anti-PD-1, anti-HER2, so we are able to treat patients with this combination, which we already did in KEYNOTE-811. Our findings in DESTINY-Gastric03 further support the idea is that we must target HER2 together with anti-PD-1 therapy to really maximize the response.

In summary, the DESTINY-Gastric03 study is ongoing. Please continue to enroll patients in it. While we were able to execute and present the initial biomarker analysis, additional biomarker analysis is ongoing. We have highlighted 20% of patients with discordance between central and HER2 and local HER2, which is important to note and to continue to investigate, and high level of PD-L1 overexpression in HER2-positive tumors, further supporting the use of dual anti-HER2, anti-PD-1 blockades in metastatic HER2-positive disease. Thank you for attending the conference. It's great to be here together in Barcelona.

Source:

Janjigian Y, Rha S, Oh D, et al. Co-occurring HER2 and PD-L1 expression in patients with HER2-positive trastuzumab-refractory gastric cancer (GC)/gastroesophageal junction adenocarcinoma (GEJA): Biomarker analysis from the trastuzumab deruxtecan (T-DXd) DESTINY-Gastric03 trial. Presented at: ESMO World Congress on Gastrointestinal Cancer; June 29-July 2, 2022. Barcelona, Spain. Abstract SO-7.