Janjigian Reviews the Evolving Role of Anti-HER2 Agents in Advanced Gastric Cancer

HER2-targeted therapy is becoming a staple in the field of metastatic gastric cancer for the patients who can benefit. Now, emerging combinations of anti-PD-1 and anti-HER2 therapy are aiming to improve the efficacy observed with the standard-of-care (SOC) therapy trastuzumab (Herceptin).

In terms of frontline treatment, trastuzumab reserved its place as SOC based on results from the phase 3, open-label, randomized, controlled ToGA study of trastuzumab in combination with chemotherapy versus chemotherapy alone in patients with HER2-positive advanced gastric or gastroesophageal junction cancer (NCT01041404). The study was positive for the primary end point of overall survival (OS), which was 13.8 months (95% CI, 12-16) in the trastuzumab arm, versus 11.1 months (95% CI, 10-13) in the chemotherapy only arm (HR, 0.74; 95% CI; 0·60–0·91; P =.0046). The trial findings established trastuzumab as the SOC for both patient populations.¹

Since ToGA, however, multiple studies of trastuzumab have reported negative results. Due to these failed trials, hope for this patient population now exists primarily in the second-line setting.

Promise was indeed observed with trastuzumab deruxtecan in the second-line setting of HER2-positive advanced gastric metastatic gastric cancer in the DESTINY-Gastric01 clinical trial (NCT03329690). OS with trastuzumab deruxtecan was 12.5 months compared with only 8.4 month with the chemotherapy control (HR, 0.59; 95% CI 0.39 to 0.88; P =.01).²

In an interview with Targeted Oncology following a virtual presentation for the 17th Annual Meeting of the International Society of Gastrointestinal Oncology, Yelena Y. Janjigian, MD medical oncologist and chief of the Gastrointestinal Oncology Service at Memorial Sloan Kettering Cancer Center, provided an overview of the role of HER2-targeted therapies in advanced gastric cancer. She also explained the importance of biomarker testing in this space.

TARGETED ONCLOGY: Can you provide an overview of your presentation at ISGIO 2020?

Janjigian: I discussed the role of HER2-targeted therapy in metastatic gastric cancer as well as the emerging data for combination therapy with anti-PD-1/anti-HER2 therapy. I also discussed the biomarker data that helps enriched population of patients that mostly will benefit from HER2 directed therapies in both the metastatic and the adjuvant early-stage setting.

TARGETED ONCOLOGY: Which anti-HER2 agents are showing promising in the patients? Which agents are emerging?

Janjigian: The standard therapy in clinical practice remains be trastuzumab in the first-line setting for HER2-positive disease based on the results of the TOGA study.The data up-to-date in the metastatic setting have been disappointing with several negative trials in the space. This year, however, we’ve seen several promising studies, particularly with combinations in the third-line setting. There was a study with the antibody-drug conjugate, trastuzumab deruxtecan (Enhertu) that was recently published in the New England Journal of Medicine. Trastuzumab deruxtecan is a promising agent that is under exploration in the second-line setting of metastatic gastric cancer in the United States.

Other agents that are quite promising are capmatinib (Tabrecta), which is a small molecule tyrosine kinase inhibitor that is under development in combination with trastuzumab. There are other agents in combination with the HER2 inhibitor margetuximab. We also have the combination of trastuzumab and pembrolizumab (Keytruda) under investigation in the phase 3 KEYNOTE-811 study.

TARGETED ONCOLOGY: What did you discuss regarding biomarker testing in patients with HER2-positive breast cancer during your presentation for ISGIO?

Janjigian: In my presentation, I reviewed the recent developments in the perioperative setting with the R2G102 study comparing trastuzumab plus chemotherapy radiation to the standard of care CROSS regiment. Unfortunately, there was no benefit for trastuzumab plus chemoradiation and I review the factors that may have contributed to this negative study.

In addition, I reviewed the data in the phase 2 and 3 setting for trastuzumab-refractory patients treated with trastuzumab deruxtecan in the third-line setting, explored in the DESTINY-Gastric 01 study.

TARGETED ONCOLOGY: What ae the key challenges with biomarker testing in this population?

Janjigian: HER2 testing in most academic centers is very routine in the first-line setting because trastuzumab is readily available to our patients. However, in the rest of the world, HER2 testing is still not routinely done in the first-line setting in patients with metastatic esophageal and gastric adenocarcinoma.

It is important to highlight that trastuzumab and HER2-directed therapies are practice-changing and are standard in this disease. Furthermore, after progression on trastuzumab, it’s important to note that up to 20% to 30% of patients have tumors that lose HER2 expression. Before oncologists decide what do for their patients in the second-line setting, particularly as HER2-directed therapies are becoming increasing available, should confirm that HER2 is still are target.

TARGETED ONCOLOGY: How do the challenges with biomarker testing differ in community centers versus academic centers?

Janjigian: In the academic setting, often we have ample tissue available for biomarker testing. We find that next-generation sequencing gives us a broader view and understanding of the biology. We know that in gastric cancer, similar colon cancer, if you have RAS alterations or RAS drivers in the tumor that is also HER2 amplified, the duration of response may not be as great and the progression-free survival is shorter when HER2 is not the true driver. That's an important distinction. Increasingly as next-generation sequencing is becoming approved and routinely used both academic and clinical practice settings, it’s critical to make sure that you work on getting on stained slides and extra tissue on the tumor sample, because both immunohistochemistry and NGA can facilitate understanding of the biology for HER2-directed therapies but also may help us in the future with monitoring for minimal residual disease or escape mechanisms using tumor-matched circulating tumor DNA analysis.

Having that liquid biopsy but also knowing the tumor mutation profile is powerful and helps us understand the mechanisms of resistance and may in the future help us identified the early progressors before the patient shows radiographically increasing to disease burden and clinical deterioration.

TARGETED ONCOLOGY: What is you key takeaway from this presentation?

Janjigian: 2020 was a transformative time in upper gastrointestinal malignancies in both HER2-positve and the HER2-negative space with anti-PD-1 therapies showing promise in the front-line setting. This is an exciting renaissance in research and development and our clinicians and patients are fortunate to have this body of work coming forward. We have to keep working and enrolling patients on studies to advance [cancer] care.

_References:

_{1. Bang YJ, Cutsem EV, Feyereislova A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. The Lancet. 2010; 376 (9742): 687-697. doi: 10.1016/S0140-6736(10)61121-X}

_{2. Shitara K, Bang YJ, Iwasa S, et al. Trastuzumab deruxtecan in previously treated her2-positive gastric cancer. N Engl J Med. 2020; 382:2419-2430. doi: 10.1056/NEJMoa2004413}