Advances in pancreatic cancer treatment

Anti-claudin 18.2 therapies have shown promising activity in gastric and gastroesophageal junction (GEJ) cancers. Clinical data from pivotal trials, such as the phase II/III SPOTLIGHT and GLOW studies evaluating zolbetuximab, an anti-claudin 18.2 monoclonal antibody, have demonstrated improved outcomes in patients with advanced claudin 18.2-positive gastric/GEJ adenocarcinoma when combined with standard chemotherapy backbones [1, 2].

Claudin 18.2 (CLDN18.2) seems to be emerging as an interesting target for the treatment of pancreatic cancer. CLDN18.2 is expressed in a significant portion (60%) of PDAC cases, making it a viable target for novel therapies. This year at ASCO, three abstracts were presented for this target [3‐5].

One of these studies was presented by Hao et al. which explored the safety and preliminary efficacy of IBI389, a bispecific antibody targeting CLDN18.2 and CD3, in patients with advanced PDAC. IBI389 aims to induce immune synapse formation between T cells and tumor cells, thereby promoting an antitumor response [5].

This phase I trial enrolled 64 patients with advanced, refractory, or metastatic CLDN18.2-positive PDAC who had failed standard treatments. All patients had received prior therapy with a median of 2 lines (range: 1 to 5). IBI389 was applied at varying doses (5–600 mg/kg) via intravenous administration, with a step-up dosing strategy for higher dose levels. The primary endpoint was safety, while secondary endpoints included objective response rate (ORR) and disease control rate (DCR) according to RECIST v1.1 criteria.

In this trial, claudin 18.2 expression was determined by immunohistochemistry using a validated, standardized assay. A prespecified cutoff for positivity was established based on ≥ 10% of tumor cells demonstrating moderate-to-strong membranous staining (≥ 2+ intensity).

Patients defined as having “high” claudin 18.2 expression typically met or exceeded this 10% threshold at ≥ 2+ intensity. Of the patients, 96.9% experienced treatment-related adverse events (TRAEs), whereby 54.7% were grade ≥ 3 TRAEs. The most common severe TRAEs included increased gamma-glutamyl transferase, decreased lymphocyte count, and nausea. Cytokine release syndrome was noted in 51.6% of patients, though none were grade ≥ 3. Preliminary efficacy data showed an ORR of 30.4% and a DCR of 69.6% in patients with high CLDN18.2 expression, suggesting promising antitumor activity. The median duration of response (DoR) and progression-free survival (PFS) were not reached.

IBI389 demonstrates a promising efficacy in heavily pretreated PDAC patients, particularly those with high CLDN18.2 expression. Further studies are warranted to confirm these findings and optimize dosing strategies and the management of TRAEs.

Previous trials have already addressed the treatment of elderly patients with advanced/metastatic PDAC, but none have prospectively compared gemcitabine and nab-paclitaxel with the 5‑fluorouracil (5-FU), leucovorin, and liposomal irinotecan FOLFIRILIP regimen [6‐8]. The GIANT trial, led by Dotan et al., has taken on this task and prospectively randomized these two chemotherapy regimens—both regimens applied on a biweekly basis [9].

In the GIANT trial, the study population was defined as “elderly” if patients were aged ≥ 70 years at the time of study entry. The study enrolled 176 elderly patients with newly diagnosed metastatic PDAC, assessing overall survival (OS) as the primary endpoint, with secondary endpoints including PFS, response rate (RR), safety, and quality of life (QOL). Median age of enrolled patients was 77 (range 70–90), 49% women, 24% ECOG‑0, 64% ECOG‑1 and 12% ECOG‑2.

While the GIANT study enrolled older patients (≥ 70 years) with metastatic pancreatic cancer, it is important to note that nearly a quarter (24%) of participants had an ECOG performance status of 0, indicating that some patients were physiologically robust despite their advanced age. Given that the regimens were tested specifically for their tolerability and feasibility in an older population, one might question whether the “less intensive” approach could result in undertreatment for this fitter subgroup. However, the study’s primary aim was to identify regimens suitable for a broad elderly cohort, including those with vulnerabilities not fully captured by ECOG performance status alone. The choice of a “friendlier” regimen may still have clinical relevance for older patients by reducing toxicity without compromising efficacy to a substantial degree, and it could serve as a more generalizable option in routine practice. Nonetheless, for select fit older patients (e.g., ECOG 0, minimal comorbidities, robust functional status), a more intensive regimen may still be considered on an individualized basis, balancing potential added benefit with the increased risk of toxicity.

The GIANT study’s adaptation of the standard gemcitabine/nab-paclitaxel schedule—omitting day 8 administration—was primarily intended to enhance tolerability in an older population. While the traditional schedule involves doses on days 1, 8, and 15, this modification reduced treatment intensity and potentially hematologic and nonhematologic toxicities. The resulting regimen can be seen as a more “elderly-adapted” approach, still providing antitumor activity, while minimizing side effects and treatment burden. In routine clinical management, this altered schedule might serve as a template for dose and schedule modifications in older or frailer patients who may not tolerate standard regimens.

The studies presented at ASCO 2024 highlight the evolving landscape of pancreatic cancer treatment, offering new hope for improved outcomes in this challenging malignancy. The promising results from the IBI389 trial underscore the potential of novel targeted therapies targeted against CLDN18.2, while the GIANT study provides critical insights into the management of elderly and frail patients. The GABARNANCE was another large trial trying to answer the question whether neoadjuvant chemoradiotherapy is of clinical benefit; however, it did not demonstrate any significant OS difference between chemoradiotherapy and chemotherapy alone. Thus, continued research and clinical trials are essential to integrate new therapeutic strategies into standard practice.