Durvalumab Plus FLOT May Not Significantly Increase AEs in Gastric Cancer

Most adverse effects (AEs) observed in previously published interim phase 3 MATTERHORN trial (NCT04592913) results, assessing durvalumab (Imfinzi) in combination with fluorouracil, leucovorin, oxaliplatin, and docetaxel (FLOT), come from chemotherapy, according to Yelena Y. Janjigian, MD.¹

CancerNetwork® spoke with Janjigian, chief attending physician of the Gastrointestinal Medical Oncology Service at Memorial Sloan Kettering Cancer Center, about how the AE profile of durvalumab in combination with FLOT compared with that of chemotherapy alone in patients with resectable locally advanced gastric and gastroesophageal junction (GEJ) cancers.

She initially expressed that previously exhibited interim results from the phase 3 MATTERHORN trial showed that chemotherapy accounted for the majority of AEs in patients receiving durvalumab plus FLOT. Additionally, she added that immune-related AEs from anti–PD-1 or anti–PD-L1 agents happen infrequently but may be serious if observed.

Janjigian reiterated the idea that chemotherapy accounted for most AEs with combination therapy by highlighting results from the phase 2/3 FLOT-4 trial (NCT01216644).² Furthermore, she touched upon potential immune-related AEs, as well as skin toxicities, before explaining that the greatest difficulty regarding the safety profile of the durvalumab/FLOT regimen will be in administering FLOT safely.

Additionally, Janjigian supported the utilization of dose reduction and antiemetics such as olanzapine (Zyprexa) for AE management in this patient population, particularly dose reduction with or without growth factor support to help mitigate white blood cell count decreases. Citing previous success with managing the safety profile of adjuvant nivolumab with chemotherapy in patients with a high risk of recurrence from gastric or GEJ cancers, she suggested that the same could be expected from the durvalumab combination regimen in MATTERHORN.

Previous safety results from the phase 3 MATTERHORN trial revealed that the safety profile of durvalumab and FLOT were comparable with prior reports of each respective agent.

Transcript:

In terms of the [adverse] effects of chemotherapy in general, we know from the metastatic setting and also from the data that were already presented from the MATTERHORN study—which is [assessing] the FLOT plus durvalumab combination–that most of the adverse effects come from chemotherapy. The immune-related [adverse] effects from anti–PD-1 or anti–PD-L1 agents are relatively rare but could be serious.

When we think about a triplet combination, most of the [adverse] effects are from the chemotherapy because you are giving them fluoropyrimidine, oxaliplatin, and docetaxel. If an oncologist is able to give these drugs and has done that in their practice for quite some time—which we have; the [phase 2/3] FLOT-4 data came out years ago, and since then, those of us that see this disease have been using FLOT—the addition of durvalumab does not cause [many adverse] effects.

You could have immune-related [adverse] effects, which can commonly affect the skin, or other mild [adverse] effects. You could have endocrinopathies, thyroid abnormalities, and glucose metabolism abnormalities. But most of the [adverse] effects are well managed. The steepest learning curve will be managing and [administrating] FLOT safely. Certainly, that’s doable.

Dose reductions are our friend and our patients’ friend, [as well as] antiemetics––using drugs like olanzapine as an antiemetic per the ASCO guidelines. Perhaps using dose reductions and/or a growth factor support for a patient who will [experience] decreases in white blood cell count will be important.

Suffice to say, the data suggest that you could do it––that’s what we have already seen. Durvalumab maintenance, [which patients continue for 1 year following surgery], is also part of what the patients are already getting used to because of the culture of high-risk disease recurrence. We have done that with adjuvant nivolumab now, and so we do not anticipate any issues with that approach.

References

1. IMFINZI® (durvalumab)-based regimen demonstrated statistically significant and clinically meaningful improvement in event-free survival in resectable early-stage gastric and gastroesophageal junction cancers. News release. AstraZeneca. March 7, 2025. Accessed March 12, 2025. https://tinyurl.com/mr4cxyzd
2. Al-Batran SE, Homann N, Pauligk C, et al. Perioperative chemotherapy with fluorouracil plus leucovorin, oxaliplatin, and docetaxel versus fluorouracil or capecitabine plus cisplatin and epirubicin for locally advanced, resectable gastric or gastro-oesophageal junction adenocarcinoma (FLOT4): a randomised, phase 2/3 trial. Lancet. 2019;393(10184):1948-1957. doi:10.1016/S0140-6736(18)32557-1