That question took on renewed urgency at the 2024 meeting of the FDA Oncologic Drugs Advisory Committee, which re-examined the comparative efficacy of PD-1 inhibitors plus chemotherapy across PD-L1 expression levels. The committee concluded that patients whose tumors express PD-L1 at a combined positive score or tumor area positivity score of 10 or higher derive the clearest benefit from PD-1 inhibitors, while those scoring below 1 show no meaningful improvement over chemotherapy alone. The large intermediate zone between those thresholds remains contested, and even in higher-expression groups certain populations, notably patients with liver metastases, appear relatively resistant to single-target immunotherapy. Against this backdrop, a new network meta-analysis published in Cancer Reports offers the first systematic indirect comparison of a different immunotherapy architecture: cadonilimab, a tetravalent bispecific antibody that blocks both PD-1 and CTLA-4 within a single molecule.

The research team, registered in the PROSPERO repository and conducted under PRISMA guidelines, searched PubMed, Web of Science, Embase and the Cochrane Library from inception through December 31, 2024, supplementing the database results with conference abstracts from ASCO, ESMO and AACR and with FDA advisory committee documents. Their inclusion criteria were deliberately strict: only Phase III randomized controlled trials in pathologically confirmed, previously untreated, HER2-negative gastric or gastroesophageal junction cancer qualified, and every experimental arm had to combine chemotherapy with either a single-agent anti-PD-(L)1 antibody or the anti-PD-1/CTLA-4 bispecific antibody cadonilimab. From an initial pool of 4,089 publications, screening narrowed the field to eight trials that met all criteria: KEYNOTE-062, ATTRACTION-4, CheckMate-649, KEYNOTE-859, GEMSTONE-303, ORIENT-16, COMPASSION-15 and RATIONALE 305. Together these trials enrolled 7,127 patients, of whom 3,572 received chemotherapy plus an immune checkpoint inhibitor and 3,555 received chemotherapy with placebo.

Because no head-to-head trial has ever compared cadonilimab with a PD-(L)1 antibody, the investigators used a frequentist network meta-analysis, treating all platinum-fluoropyrimidine doublet backbones—XELOX, FOLFOX, SOX and fluorouracil-platinum—as a common chemotherapy comparator node, an approach supported by prior noninferiority trials and systematic reviews showing these regimens are clinically interchangeable. Overall survival, defined as time from randomization to death from any cause, served as the primary endpoint, with progression-free survival and Grade 3 to 5 treatment-related and serious adverse events as secondary measures. Risk of bias was low across the included studies when assessed with the Cochrane RoB 2 tool, and all trials were analyzed on an intention-to-treat basis. Because the network was star-shaped, with cadonilimab connected to the PD-(L)1 inhibitors only through the shared chemotherapy node, formal inconsistency testing was not possible, a structural limitation the authors acknowledge openly.

The headline finding is striking. In the intention-to-treat population, every immunotherapy regimen outperformed chemotherapy alone, but cadonilimab plus chemotherapy delivered the largest survival gain, with a hazard ratio for overall survival of 0.62 (95 percent confidence interval 0.50 to 0.77), compared with hazard ratios of 0.75 to 0.82 for the five PD-(L)1 antibodies: sugemalimab, sintilimab, pembrolizumab, tislelizumab and nivolumab. In the indirect comparison against the pooled PD-(L)1 class, cadonilimab was associated with a statistically significant 22 percent reduction in the hazard of death (hazard ratio 0.78, 95 percent confidence interval 0.62 to 0.98), with essentially no heterogeneity among trials. Treatment ranking by P-score placed cadonilimab first with a probability score of 0.9586, well ahead of the rest of the field, and progression-free survival followed the same pattern, with a hazard ratio of 0.70 (95 percent confidence interval 0.57 to 0.86) favoring the bispecific approach.

The mechanistic rationale for this advantage lies in cadonilimab’s unusual tetravalent design. Gastric adenocarcinomas commonly express the immune checkpoints PD-1 and CTLA-4, which tumors exploit to suppress T-cell responses, and preclinical work has long shown that blocking both pathways synergistically enhances antitumor immunity. Conventional combination immunotherapy with separate PD-1 and CTLA-4 antibodies, tested in the CheckMate 649 trial, was hampered by dose-limiting toxicity and failed to improve survival. Cadonilimab instead packs both binding specificities into one antibody that preferentially accumulates in tumor tissue where PD-1 and CTLA-4 are co-expressed, concentrating dual blockade at the tumor site while sparing normal tissue. That design, the authors argue, explains both the improved efficacy and the tolerability profile observed in COMPASSION-15.

Safety data appear to support that interpretation. Across the included trials, no statistically significant differences emerged between cadonilimab and PD-(L)1 inhibitors in Grade 3 or higher treatment-related adverse events (odds ratio 0.83, 95 percent confidence interval 0.54 to 1.28) or serious adverse events (odds ratio 0.89, 95 percent confidence interval 0.56 to 1.42). Egger’s tests for publication bias were non-significant across all endpoints, and leave-one-out sensitivity analyses left the direction and significance of every primary result unchanged. Still, the authors caution that the confidence intervals around the safety comparisons are wide and rest on a limited number of trials, so a clinically meaningful difference in toxicity cannot be definitively excluded.

The most consequential findings emerge from exploratory subgroup analyses. In patients with low PD-L1 expression—combined positive scores below 10—the hazard ratio for overall survival favored cadonilimab over PD-(L)1 therapy with a point estimate of 0.77 (95 percent confidence interval 0.58 to 1.01), consistent across the CPS below 1 and below 5 cutoffs, while the single-target antibodies showed little or no benefit versus chemotherapy in the same strata. Even more pronounced was the liver metastasis subgroup, where cadonilimab reduced the hazard of death by 33 percent relative to PD-(L)1 inhibitors (hazard ratio 0.67, 95 percent confidence interval 0.49 to 0.93) and halved it relative to chemotherapy alone. This matters because liver metastases deplete peripheral T cells, erode intratumoral T-cell diversity and enrich immunosuppressive regulatory T cells and macrophages, creating a microenvironment that single-agent PD-1 blockade struggles to overcome; the authors propose that simultaneous CTLA-4 inhibition, which suppresses regulatory T cells, counters this biology more effectively. Statistically significant advantages for cadonilimab also appeared in male patients and those with an ECOG performance status of 1, subgroups in which androgen-receptor signaling and heightened systemic inflammation respectively promote T-cell exhaustion that dual checkpoint blockade may more fully reverse.

The authors are careful to frame these subgroup results as hypothesis-generating. All subgroup estimates derive from study-level aggregate data rather than individual patient information, which introduces the risk of ecological bias and limits control of within-trial confounding, and the PD-L1 analyses relied on different immunohistochemistry platforms, albeit assays with demonstrated substantial to excellent concordance in gastric cancer. Ranking analyses are sensitive to network structure and cannot by themselves establish superiority. Nevertheless, the overall picture is internally consistent: for patients whose tumors express high levels of PD-L1, all immunotherapy regimens deliver clear survival benefits over chemotherapy, but for the large populations left in clinical limbo—those with low PD-L1 expression, liver metastases, or intermediate expression where regulatory debate continues—this analysis suggests that a bispecific antibody harnessing two immune escape pathways simultaneously may be the preferable first-line partner for chemotherapy. The findings stop short of Level 1 evidence, and the authors call explicitly for prospective head-to-head trials, but they mark the first quantitative indication that bispecific checkpoint engineering could redraw the treatment algorithm for advanced gastric and gastroesophageal junction cancer.

Subject of Research: Indirect comparison of cadonilimab, a PD-1/CTLA-4 bispecific antibody, versus PD-(L)1 inhibitors as first-line therapy for advanced gastric and gastroesophageal junction cancer

Article Title: Survival Outcomes With Cadonilimab Versus PD‐(L)1 Therapy in Front‐Line Gastric Cancer: A Network Meta‐Analysis

Article References: Yu, Z.-K., Yi, J.-H., Xue, J., Huang, Y.-C., Zhao, Y., Jiang, C., Yin, C.-X., Xia, B., Zhou, Y.-X., He, W.-Z., & Xia, L.-P. (2026). Survival Outcomes With Cadonilimab Versus PD ‐(L)1 Therapy in Front‐Line Gastric Cancer: A Network Meta‐Analysis. Cancer Reports, 9(9), Article e70672. https://doi.org/10.1002/cnr2.70672

Image Credits: AI Generated

DOI: 10.1002/cnr2.70672

Keywords: cadonilimab, gastric cancer, gastroesophageal junction cancer, network meta-analysis, immune checkpoint inhibitors, PD-1, CTLA-4, bispecific antibody, PD-L1 expression, liver metastasis, overall survival, COMPASSION-15

The headline result is difficult to ignore. Among 71 efficacy-evaluable patients with small cell lung cancer as of July 7, 2026, one patient achieved a complete response, 49 achieved partial responses and 16 had stable disease. That translates into an overall objective response rate of 70.4% across all dose levels tested, with a disease control rate of 93.0%. For a disease in which second-line and later therapies historically deliver single-digit to low-double-digit response rates, such figures stand out sharply. Perhaps more compelling still is how the activity held up across different lines of treatment: the response rate reached 92.3% in patients receiving the combination as first-line therapy, 77.3% in the second-line setting, and 52.4% among patients treated in the third line or later. Even among patients whose tumors had previously been treated with DLL3-targeting agents, a class of drugs developed specifically for small cell lung cancer, the objective response rate was 70.0%, indicating that the combination retains activity after prior targeted therapy.

Adam Schoenfeld, M.D., of Memorial Sloan Kettering Cancer Center in New York, the presenting author of the study, emphasized the breadth of the observed benefit. The early activity, he noted, was encouraging in part because responses were seen across multiple lines of therapy in small cell lung cancer, and together with the manageable safety profile, the findings support further clinical development of the combination. That framing matters, because in early-phase oncology trials, enthusiasm is often tempered by the question of whether efficacy signals come at the cost of unacceptable toxicity. In this study, the investigators concluded that the balance was favorable enough to justify advancing the regimen into further clinical testing.

The trial itself, BNT324-01, is a global Phase 1b/2 study evaluating the efficacy and safety of the pumitamig and elfetabart drozuntecan combination in patients with advanced or metastatic small cell lung cancer and non-small cell lung cancer. The design follows the classic architecture of modern early-phase oncology development: a dose escalation phase to establish safety and identify biologically active dose levels, a backfill cohort to gather additional safety and pharmacologic data at selected doses, and a subsequent dose expansion phase intended to support optimal dose selection. The primary endpoints are objective response rate and safety, the twin pillars on which early clinical proof of concept is typically judged. As of June 2, 2026, 193 patients with either small cell lung cancer or non-small cell lung cancer had received the combination, providing a substantial body of safety data for a program at this stage of development.

On the safety front, the data paint a picture of a regimen that is active but not without side effects, as expected for a combination of two potent anticancer agents. No dose-limiting toxicities occurred during the dose escalation phase, an important signal that the doses under study could be administered without triggering the severe, protocol-halting toxicities that often derail combination programs. Treatment-related adverse events occurred in 75.6% of patients, and grade 3 or higher treatment-related events were reported in 23.3%. The most common treatment-related events were gastrointestinal or hematologic in nature, and the vast majority were grade 1 or 2 in severity, meaning they were mild to moderate and generally manageable with standard supportive care. For clinicians weighing whether to expose patients with limited treatment options to a novel dual-agent regimen, that toxicity profile will be a central consideration.

Understanding why this combination is scientifically interesting requires a look at the biology of each component. Pumitamig is a bispecific antibody engineered to engage two targets simultaneously: PD-L1, the immune checkpoint ligand through which many tumors suppress T-cell activity, and VEGF-A, a key driver of tumor angiogenesis and an immunosuppressive factor in the tumor microenvironment. By blocking both pathways with a single molecule, bispecific antibodies of this class aim to relieve immune suppression while also normalizing the tumor vasculature, potentially improving immune cell infiltration into tumors. This dual mechanism reflects a broader trend in immuno-oncology, in which checkpoint inhibition is increasingly paired with strategies that remodel the tumor microenvironment rather than simply unleashing T cells in isolation.

Elfetabart drozuntecan, by contrast, belongs to the antibody-drug conjugate class, often described as guided chemotherapy. The molecule pairs an antibody directed against B7H3, a cell surface protein abundantly expressed on many solid tumors including small cell lung cancer, with a cytotoxic payload delivered selectively to B7H3-expressing cancer cells. The rationale for combining the two agents is mechanistically coherent: the antibody-drug conjugate delivers direct tumor cell killing, which can release tumor antigens and provoke immunogenic cell death, while the bispecific antibody works to sustain an active antitumor immune response and disrupt the vascular and checkpoint defenses tumors use to escape. Combining a T-cell-engaging checkpoint bispecific with an antibody-drug conjugate is an emerging strategy across oncology, and the BNT324-01 data represent the first clinical evidence that this particular pairing can work in lung cancer patients.

Beyond the imaging-based response measurements, the trial also generated molecular evidence of early activity through circulating tumor DNA analysis, a technique increasingly used to detect treatment effect weeks or months before conventional scans can. Among evaluable patients, 96% had confirmed reduction in circulating tumor DNA from baseline by cycle 3, day 1, and 39% achieved ctDNA clearance, meaning fragments of tumor-derived DNA became undetectable in the blood. Molecular response of this kind is often associated with durable clinical benefit, and the high rate of ctDNA reduction suggests that the biological activity of the combination begins early in the course of treatment. For a disease as fast-moving as small cell lung cancer, where tumor burden can double in a matter of weeks, early molecular confirmation of activity is a particularly meaningful signal.

Several caveats temper the excitement. The data are early, the trial is ongoing, and the patient numbers, while respectable for a Phase 1b/2 study, are not yet sufficient to establish how durable the responses will be or how the combination will compare against standard-of-care regimens in randomized settings. The investigators also noted that the non-small cell lung cancer data from the trial remain immature and will be reported separately, leaving open the question of whether the combination’s activity extends beyond small cell histology. It is also disclosed that Dr. Schoenfeld has financial interests related to BioNTech, the company developing both agents, a common arrangement in industry-sponsored early-phase research that readers should weigh when interpreting investigator enthusiasm.

Nevertheless, the BNT324-01 results mark a notable moment for a disease that has seen only incremental progress for decades. Small cell lung cancer accounts for roughly 10 to 15 percent of lung cancers and is strongly associated with smoking, with most patients diagnosed at an advanced stage where five-year survival remains grim. The field has recently been energized by DLL3-targeted bispecific antibodies and antibody-drug conjugates, and the present data suggest that pairing a PD-L1 x VEGF-A bispecific with a B7H3-directed conjugate may offer a complementary, non-cross-resistant strategy, including for patients whose tumors have already progressed on DLL3-directed therapy. If the encouraging response rates and manageable toxicity observed to date are confirmed as the trial matures and moves toward later-phase testing, the combination could become a serious contender in the treatment landscape of one of medicine’s most challenging cancers. For now, clinicians and patients alike will be watching closely as the dose expansion data and the non-small cell lung cancer results emerge in the months ahead.

Subject of Research: A Phase 1b/2 clinical trial evaluating pumitamig plus elfetabart drozuntecan in small cell lung cancer

Article Title: Pumitamig plus elfetabart drozuntecan shows encouraging early activity in small cell lung cancer

Article References: Pumitamig plus elfetabart drozuntecan shows encouraging early activity in small cell lung cancer. (n.d.). Original publication

Image Credits: AI Generated

DOI: Not provided

Keywords: small cell lung cancer, pumitamig, elfetabart drozuntecan, bispecific antibody, antibody-drug conjugate, B7H3, PD-L1, VEGF-A, BNT324-01 trial, IASLC WCLC 2026, immuno-oncology, circulating tumor DNA