Antibody-Drug Conjugates and Immunotherapy Combinations: What is Next?

By Nataliya Uboha, MD, PhD, Zev Wainberg, MD, MSc, Suneel Kamath, MD, Sunnie Kim, MD - Last Updated: March 19, 2025

A roundtable discussion, moderated by Nataliya Uboha, MD, PhD, discussed the current treatment considerations for gastric cancer, GEJC, and ESCC, as well as relevant clinical trial data from the 2025 American Society of Clinical Oncology Gastrointestinal Cancers Symposium. Dr. Uboha was joined by Zev Wainberg, MD, MSc; Suneel Kamath, MD; and Sunnie Kim, MD.

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In the final segment of the roundtable series, the panel covers the ASPEN-O6 trial’s non-practice-changing results, ongoing excitement around ADCs like zanidatamab in late-line HER-2 and Claudin-positive cancers, and promising data on tislelizumab in esophageal squamous cell cancer, including debate on chemotherapy backbones, CPS cutoffs, and the need for streamlined biomarker guidelines.

View the previous segments of the roundtable discussion.

Dr. Uboha: Should we switch to second-line treatments? Speaking of HER2-positive disease, we saw the results of the ASPEN-O6 trial today. I think you were one of the co-authors. Would you like to summarize the data?

Dr. Wainberg: It’s a challenging dataset to interpret because it involved a second-line patient population with a non-standard control: trastuzumab, ramucirumab, and paclitaxel (RAM-PAC) combined with trastuzumab. The trial aimed to assess the contribution of the CD47 antibody, evor. We did see a higher response rate with four drugs compared to three, but questions remain: Do we need trastuzumab at all, and does the contribution of components justify a phase 3 study? This is especially relevant since the trial launched before T-DXD became standard. Along with upcoming T-DXD vs. RAM-PAC randomized data, we’ll soon have more second-line HER2 data to discuss.

Dr. Uboha: I’m still processing the results. The higher response rate was encouraging, but it didn’t meet the primary endpoint. Using four drugs simultaneously—some administered weekly—is difficult for patients. Competing against an antibody-drug conjugate given once every three weeks is tough.

Dr. Wainberg: Twenty percent of patients had received treatment in the third line. It’s hard to convey all the nuanced data in a five-minute presentation, but 15 to 20% had prior T-DXD exposure. Your point about the control arm is valid.

Dr. Uboha: My understanding was that trastuzumab had to be included due to the drug’s mechanism of action. Interesting data, though not practice-changing. The question is whether it warrants larger studies. Anything exciting at this meeting or new compounds you’re interested in for late-line settings, Dr. Kamath?

Dr. Kamath: Zani is the up-and-comer in this space. We talked about ADCs earlier; there are several Claudin ADCs in the pipeline. I’m excited to see their potential in combination with immunotherapy. Many trials are incorporating those combinations up front, which might solve the question of whether to use Claudin or IO.

Dr. Uboha: A lot of ADCs, right?

Dr. Kamath: Yes.

Dr. Uboha: In late lines—HER2 ADCs, Claudin ADCs—it’s good to have options, but nothing ready for prime time yet.

Let’s switch gears to esophageal squamous cell cancers. Tislelizumab was studied in the first line, and we’re awaiting a decision on approval. Any thoughts on its use in this setting?

Dr. Kim: It aligns well with CheckMate 648, which showed a benefit for chemo plus a PD-1 inhibitor over chemo alone, especially in PD-1-positive patients. In my experience, PD-1 inhibitors have been game-changers for esophageal squamous cell cancer, yielding long-term survivals I didn’t see before.

Dr. Uboha: I agree. It seems more immunotherapy-sensitive than even adenocarcinoma. I was happy to see a different chemo backbone in that study with tisle. What do you think, Dr. Kamath?

Dr. Kamath: Very interesting. It’s not often used in the U.S., but the outcomes seemed consistent regardless of the chemo backbone. It’s good to know that option exists.

Dr. Uboha: You don’t need a port, so patients can start treatment sooner.

Dr. Kamath: True. Rationale 306 showed a median OS difference—16 months vs. 10—that stood out more than CheckMate 648 and other Pembro trials, even though these are cross-trial comparisons.

Dr. Uboha: But we can’t ignore those numbers on the screen, right?

Dr. Kamath: Exactly. I always look at the delta, not just the medians. You can’t ignore that signal.

Dr. Wainberg: Good points; I have nothing major to add. I assume it will get approved; it lines up well, so there’s no reason it shouldn’t.

Dr. Uboha: I agree.

Dr. Kim: Can I ask your opinion on a potential CPS cutoff for squamous cell cancer versus adenocarcinoma? Do you have strong feelings about that?

Dr. Uboha: I think it should be the same as adenocarcinoma. Let’s make it simpler with a unified cutoff across upper GI tumors. In the tislelizumab study, patients with low TAP scores did worse; the hazard ratio was close to one. It doesn’t make sense to use it there. Simpler guidelines would help pathologists and community partners.

Dr. Kim: It’s a smaller population, but I saw that detriment in the forest plot.

Dr. Uboha: I used to think we should give it to everyone, but the subgroup data changed my mind. Still, most first-line squamous cell patients had PD-1-positive tumors.

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