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Associate Attending Physician
Chief, Gastrointestinal Oncology Service
Memorial Sloan Kettering Cancer Center
Associate Professor of Medicine
Weill Cornell Medical College
New York, New York
Yelena Y. Janjigian, MD, has disclosed that she received funds for research support from Bayer, Boehringer Ingelheim, Bristol-Myers Squibb, Genentech/Roche, Lilly, and Merck; has received consulting fees from AstraZeneca, Bayer, Bristol-Myers Squibb, Daiichi-Sankyo, Imugene, Jounce, Lilly, Merck Serono, ONO, Pfizer, Seattle Genetics, and Zymeworks Inc.; and has an ownership interest in Rgenix.
Trastuzumab deruxtecan was approved by the FDA in January 2021 for the treatment of adult patients with locally advanced or metastatic HER2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma who have received a previous trastuzumab-based regimen. In this commentary, I discuss the data supporting this approval and how I plan to incorporate trastuzumab deruxtecan into my clinical practice.
For patients with advanced gastric or GEJ cancers, chemotherapy is the standard of care in the first-line setting, most commonly including fluoropyrimidine and platinum agents. It is estimated that 15% to 20% of patients with gastroesophageal cancers have HER2-positive disease, and it was demonstrated in the phase III ToGA trial that adding trastuzumab to chemotherapy improves outcomes for patients with advanced HER2-positive gastric cancer. This has become standard treatment practice for these patients.
In recent years, numerous additional HER2-targeted agents have been assessed as part of first-line and second-line combination therapy regimens for patients with advanced gastric cancers; unfortunately, no improvements in outcomes were observed with these regimens until the DESTINY-Gastric01 study of trastuzumab deruxtecan.
Trastuzumab Deruxtecan: DESTINY-Gastric01
Trastuzumab deruxtecan is a novel antibody–drug conjugate that comprises a humanized anti-HER2 monoclonal antibody (with the same amino acid sequence as trastuzumab) linked to a topoisomerase I inhibitor payload. This agent was approved for use in gastric/GEJ cancers based on the phase II DESTINY‑Gastric01 study, in which 188 patients with HER2-positive locally advanced/metastatic gastric or GEJ cancer with progressive disease on ≥ 2 previous regimens were randomized to trastuzumab deruxtecan or physician’s choice chemotherapy (irinotecan or paclitaxel). Of note, it was not mandated that patients have the HER2 positivity of their tumor confirmed at the time of progression, although HER2 amplification in archival tumor tissue was required.
In terms of efficacy, the response rate and survival were remarkable for later-line treatment of advanced gastric/GEJ cancer. The ORR was 51.3% with trastuzumab deruxtecan vs 14.3% with physician’s choice chemotherapy; correspondingly, OS was 12.5 months vs 8.4 months, respectively.
The toxicity profile was generally as expected with an irinotecan‑like topoisomerase I inhibitor. Of note, trastuzumab deruxtecan had been associated with interstitial lung disease in previous studies, and 9.6% of patients experienced this adverse event in DESTINY-Gastric01 (vs 0% with physician’s choice chemotherapy).
How I Plan to Use Trastuzumab Deruxtecan in My Practice
It should be noted that DESTINY-Gastric01 included only patients who had already received ≥ 2 previous therapies. However, in the United States, trastuzumab deruxtecan is indicated for any patient who has received a previous trastuzumab-based regimen. This is an interesting caveat and certainly a welcome chance and opportunity to use this agent in more of our patients with metastatic HER2‑positive gastric/GEJ cancers.
As DESTINY-Gastric01 had a population of patients who received trastuzumab deruxtecan as third-line therapy or beyond, we do not actually have randomized data with this agent as a second-line therapy. Based on this, I might consider, if possible, a promising trial of experimental therapy vs trastuzumab deruxtecan in the second‑line setting, and then use trastuzumab deruxtecan as third-line therapy for those patients who had not yet received this agent. As we tell our patients, treatment is a marathon, not a sprint, and the more options you have, the better. The single-arm, phase II DESTINY-Gastric02 study will report on the use of trastuzumab deruxtecan in the second‑line setting for patients who received a previous trastuzumab-based regimen.
It is important to take HER2 testing into account when considering treatment with this agent. In the FDA label, reassessment of HER2 status via a repeat biopsy is recommended if this is deemed clinically feasible and safe. It is thought that 20% to 30% of patients lose HER2 expression in their tumor after disease progression on trastuzumab, and other factors—such as HER2 tumor heterogeneity and low levels of HER2 expression—can affect the degree to which a patient may benefit from second‑line HER2‑directed therapy. As such, it is important to confirm that HER2 is still amplified in the tumor whenever possible. I generally consider whether the patient ever benefited from trastuzumab‑based therapy in the context of HER2 testing. Was the patient’s disease primary refractory to trastuzumab‑based therapy? Rapid disease progression on this therapy may suggest that a patient’s disease is less HER2 driven. In those cases, a biopsy would be particularly advised. Noninvasive ways of measuring HER2 expression may also be considered for some cases; these include using liquid biopsy to measure and follow HER2 amplification with circulating tumor DNA in the patient’s plasma. These methods can give us some reassurance in using trastuzumab deruxtecan in second‑line or third-line settings. If a patient is found to have HER2-negative disease, there are certainly other options, including ramucirumab plus paclitaxel.
Additional clinical factors should also be considered before deciding if trastuzumab deruxtecan is appropriate for your patient. As mentioned above, interstitial lung disease has been reported in patients treated with trastuzumab deruxtecan, so it is very important to monitor for symptoms of this adverse event in patients treated with this agent. For patients with underlying lung disease or a history of pneumonitis, alternatives to trastuzumab deruxtecan should be considered.
Numerous additional treatment strategies are being assessed in clinical trials for treating patients with HER2-positive advanced gastric/GEJ cancers. The phase II/III MAHOGANY trial is assessing margetuximab (a HER2-targeted antibody with enhanced antibody-dependent cell-mediated cytotoxicity vs trastuzumab) in several combination approaches as first-line treatment for patients with advanced HER2-positive gastric/GEJ cancers. Combination approaches with trastuzumab, pembrolizumab, and chemotherapy have also shown promise as first-line treatment and are now being further assessed in the phase III KEYNOTE-811 study.
How will you use trastuzumab deruxtecan for your patients with advanced HER2-positive gastric/GEJ cancers? Answer the polling question and join the conversation by posting a comment in the discussion section.