At the American Society of Clinical Oncology (ASCO) 2025 Annual Meeting held in June, progress in the treatment of gastrointestinal (GI) cancers took center stage, with several late-breaking abstracts and plenary sessions focused on trials in colorectal, gastric, and gastroesophageal malignancies. In an interview with Targeted OncologyTM, Patrick Boland, MD, medical oncologist specializing in GI cancers at The Rutgers Cancer Institute of New Jersey, discussed some of the biggest abstracts in the space from the meeting.
ATOMIC: Atezolizumab Plus mFOLFOX6 in dMMR Colon Cancer
The phase 3 ATOMIC trial (NCT02912559) investigated whether adding atezolizumab (Tecentriq), an anti-PD-L1 antibody, to standard adjuvant mFOLFOX6 chemotherapy could improve outcomes for patients with surgically resected stage III colon cancer with deficient mismatch repair (dMMR).1 This patient population is known to have some resistance to fluoropyrimidines and has shown benefit from immune checkpoint inhibitors in the metastatic setting.
“These dMMR, MSI-high patients represent probably 10% to 20% of all early-stage colon cancers and about 10% of stage III colon cancers. We know in the metastatic setting that this class of drugs is highly active, and there [are] data that the PD-1 inhibitors have better efficacy than chemotherapy in the metastatic space. So, it’s natural to look at this in the postoperative space: can we cure more patients after surgery?” Boland said in the interview.
The study randomly assigned 712 patients to either mFOLFOX6 plus atezolizumab for 6 months followed by atezolizumab monotherapy for an additional 6 months, or mFOLFOX6 alone for 6 months. At a median follow-up of 37.2 months, the results demonstrated a statistically significant improvement in disease-free survival (DFS) for the atezolizumab arm. The 3-year DFS was 86.4% in the atezolizumab arm compared with 76.6% in the mFOLFOX6 alone arm, representing a 50% reduction in the risk of recurrence or death (HR, 0.50; 95% CI, 0.35-0.72; P <.0001). The benefits were consistent across various subgroups, including older patients and those with low- or high-risk disease.
While treatment-related grade 3 or higher adverse events (AEs) were slightly more common in the atezolizumab arm (71.7% vs 62.1%), the safety profile was manageable and consistent with known toxicities of the individual agents.
“I think it immediately changes the standard, once the regulatory bodies act as they should,” Boland said. “I would expect an approval, and I would expect this is going to become standard of care in clinic for patients who don’t have a contraindication to the addition of immunotherapy.”
Despite these promising findings, Boland still has questions about the regimen and its potential use in the real world.
“One question is whether [patients] truly need that full 6 months of treatment,” Boland said. “I think something [else] we will ultimately benefit from is information on [if there are] patients who could get immunotherapy and not chemotherapy.”
“[A] problem is that our imaging-based staging is suboptimal. So, there is significant risk with neoadjuvant treatment that patients who are [at] low risk for recurrence get an immunotherapy drug which does carry some risks. It’s going to be a balancing act, and there’s more work that needs to be done,” Boland said.
MATTERHORN: Durvalumab Plus FLOT in Gastric/GEJ Cancer
The phase 3 MATTERHORN study (NCT04592913) investigated the efficacy and safety of adding durvalumab (Imfinzi), an immune checkpoint inhibitor, to the standard perioperative FLOT chemotherapy regimen (fluorouracil, leucovorin, oxaliplatin, and docetaxel) for patients with resectable gastric or gastroesophageal junction (GEJ) cancer.2 Despite FLOT being standard of care, recurrence rates remain high, prompting exploration of immunotherapy combinations.
“This is a patient group that is at quite high risk of recurrence,” Boland explained. “Perioperative treatment…has been the standard for some time now, with FLOT being the standard for patients who are fit enough to receive it, and many patients receiving regimens like FOLFOX that are less aggressive than FLOT due to fitness… We knew that similarly, the PD-L1–targeting drugs, or PD-1/PD-L1 axis-targeting drugs, improve outcomes in the metastatic space. So, it’s a natural question here: Can we improve outcomes by adding these in the perioperative space?”
MATTERHORN randomly assigned 948 patients to receive either durvalumab plus FLOT or placebo plus FLOT, administered both before (neoadjuvant) and after (adjuvant) surgery, followed by durvalumab or placebo monotherapy. The primary end point was event-free survival (EFS). The results demonstrated a statistically significant improvement in EFS for the durvalumab-FLOT arm, with a hazard ratio of 0.71 (P <.001) and the median EFS not yet reached (95% CI, 40.7-NR), compared with 32.8 months for the placebo-FLOT arm (95% CI, 27.9-NR). An encouraging trend towards improved overall survival (OS) was also observed. Importantly, the addition of durvalumab did not increase the rates of severe AEs or delay surgical procedures or subsequent adjuvant therapy.
“There was a significant improvement in disease-free survival. It looks like it may translate to a smaller overall survival difference. But given the suboptimal outcome of these patients, I think this will be a standard moving forward,” Boland said.
Boland highlighted 2 quandaries he still has regarding the MATTERHORN data.
“There’s a little bit of a dilemma in this space, and I think we still do not fully know how to use the PD-L1 biomarker in the neoadjuvant and adjuvant space[s]. Some data would suggest it matters. At least the data presented thus far in this study suggested PD-L1 did not matter. I think it would still be helpful to see a further PD-L1 breakdown by range.”
Boland also noted that this regimen is not suited for all patients, raising further questions. “The issue I think we are going to run into in clinic immediately is because many patients are not candidates for FLOT, what are we doing for them? Moving forward, we need more information there, and are there, perhaps, modifications [that] can be made to FLOT to improve tolerability while maintaining the efficacy? I do share some concerns that there may be a move where patients end up getting FOLFOX and durvalumab, which is not really what this study showed. And we have a negative platinum doublet and PD-1 study already.”
DESTINY-Gastric04: T-DXd in Gastric/GEJ Cancer
The DESTINY-Gastric04 trial (NCT04704934) was a global, randomized phase 3 study designed to evaluate the efficacy and safety of trastuzumab deruxtecan (T-DXd; Enhertu) compared with ramucirumab (Cyramza) plus paclitaxel in patients with HER2-positive unresectable or metastatic gastric or GEJ adenocarcinoma.3 This study focused on patients who had already received a prior trastuzumab-based regimen, addressing a critical need for effective second-line therapies in this setting.
The results, based on a planned interim analysis, demonstrated a statistically significant and clinically meaningful improvement in OS with T-DXd. Patients treated with T-DXd achieved a median OS of 14.7 months compared with 11.4 months for those receiving ramucirumab/paclitaxel, representing a 30% reduction in the risk of death (HR, 0.70; P =.0044).
“Essentially, this study showed us that the outcomes were better when you look at response rate, progression-free survival, and overall survival with use of trastuzumab deruxtecan over paclitaxel and ramucirumab, and that quality of life was preserved. I think there were no surprising new adverse events…. It is a positive study, and I think it reinforces something that we’ve largely already been doing in clinic,” Boland said.
While treatment-emergent AEs were common in both arms, the safety profile of T-DXd was consistent with previous studies, with no new safety signals. Notably, interstitial lung disease/pneumonitis, a known side effect of T-DXd, occurred in 13.9% of patients in the T-DXd arm, mostly low grade.
“The other thing we think about [with] HER2-targeting drugs [is] cardiotoxicity. They did not see any increase with this regimen vs ramucirumab-paclitaxel, so that is reassuring,” Boland added.
These compelling results firmly establish T-DXd as a new second-line standard of care for patients with HER2-positive unresectable/metastatic GC/GEJA. Boland did highlight that HER2 targeting, while perhaps most known in breast cancer, is different in gastric cancer.
“HER2-targeting is different in gastric cancer as compared [with] breast cancer, where the whole HER2 targeting story really first came into play,” Boland noted. “This study required that patients had HER2 retesting upfront. While some experts have been advocating it for some time, I think there’s some real debate overall as to, do we do that for every patient? I think that question remains, but I think as evidence builds, I think that should be pushing us to look at retesting more routinely as possible. At the very least, it merits a discussion with patients.”
REFERENCES:
1. Sinicrope FA, Ou FS, Peters W, et al. Randomized trial of standard chemotherapy alone or combined with atezolizumab as adjuvant therapy for patients with stage III deficient DNA mismatch repair (dMMR) colon cancer (Alliance A021502; ATOMIC). J Clin Oncol. 43, LBA1-LBA1(2025). doi:10.1200/JCO.2025.43.17_suppl.LBA1
2. Janjigian YY, Al-Batran SE, Wainberg ZA, et al. Event-free survival (EFS) in MATTERHORN: A randomized, phase 3 study of durvalumab plus 5-fluorouracil, leucovorin, oxaliplatin and docetaxel chemotherapy (FLOT) in resectable gastric/gastroesophageal junction cancer (GC/GEJC). J Clin Oncol. 43, LBA5-LBA5(2025). doi:10.1200/JCO.2025.43.17_suppl.LBA5
3. Shitara K, Gumus M, Pietrantonio F, et al. Trastuzumab deruxtecan (T-DXd) vs ramucirumab (RAM) + paclitaxel (PTX) in second-line treatment of patients (pts) with human epidermal growth factor receptor 2-positive (HER2+) unresectable/metastatic gastric cancer (GC) or gastroesophageal junction adenocarcinoma (GEJA): Primary analysis of the randomized, phase 3 DESTINY-Gastric04 study. J Clin Oncol. 43, LBA4002-LBA4002(2025). doi:10.1200/JCO.2025.43.17_suppl.LBA4002
