RC148 Plus Chemotherapy in Frontline NSCLC: A Q&A With Yuanyuan Zhao, MD

PD-1 inhibition plus platinum-based chemotherapy remains the first-line standard for driver-negative advanced non–small cell lung cancer (NSCLC), but a substantial share of patients progress within the first year. The PD-1/VEGF bispecific class has moved quickly to challenge that backbone: ivonescimab plus chemotherapy improved overall survival (OS) over tislelizumab plus chemotherapy in squamous disease in the phase 3 HARMONi-6 trial, and pumitamig plus chemotherapy has produced encouraging frontline activity in the global ROSETTA Lung-02 program.

At the IASLC 2026 World Conference on Lung Cancer (WCLC) in Seoul, investigators presented phase 1b data from the RC148-C002 study of RC148 (ABBV-1480), a PD-1/VEGF bispecific antibody developed by RemeGen and licensed to AbbVie outside Greater China, in combination with platinum-based chemotherapy in previously untreated locally advanced or metastatic NSCLC.1

At the 10 mg/kg dose, identified as the recommended phase 3 dose for combination regimens in both histologies, the objective response rate was 90.0% in squamous NSCLC (n = 27) and 75.9% in nonsquamous NSCLC (n = 22). The most common treatment-related adverse events were decreases in white blood cell, neutrophil, and platelet counts and anemia, and no grade 3 or higher hemorrhage was observed with the 10 mg/kg combinations.2 A phase 3 trial of RC148 plus chemotherapy in first-line squamous NSCLC is under way, and a global phase 3 program sponsored by AbbVie has been cleared to begin.

In an interview with OncLive®, study author Yuanyuan Zhao, MD, chief physician at Sun Yat-sen University Cancer Center in Guangzhou, China, discussed the rationale for pairing RC148 with chemotherapy, what differentiates the molecule from other PD-1/VEGF bispecifics, the safety profile in squamous disease, and what the next phase of development must show.

OncLive: Frontline NSCLC treatment is a competitive landscape, and the PD-1/VEGF bispecific class has advanced quickly over the past 2 years. What was the specific rationale for pairing RC148 with chemotherapy in the first-line setting, and what were you most hoping to learn from this study?

Zhao: The main rationale was that PD-1 inhibitors plus chemotherapy, while the standard of care, still leave many patients progressing within the first year, and OS remains limited. Over the past 2 years, the PD-1/VEGF bispecific class has shown that dual targeting may offer greater clinical benefit, and RC148 is designed to be a differentiated PD-1/VEGF bispecific antibody that delivers both mechanisms in one agent. What we most hoped to learn was whether adding RC148 to chemotherapy could improve upon the current PD-1 plus chemotherapy backbone and potentially become a new first-line standard, with meaningful improvements in response and durability and a manageable safety profile.

What were the most implicative findings toward treatment strategy? How does it change practice and approach?

The most important finding was the robust and durable antitumor activity of RC148 plus chemotherapy, with encouraging depth and duration of response. The safety profile was manageable, and the incidence of immune-related adverse events and VEGF-related toxicities, particularly grade 3 or higher events, was low.

Importantly, benefit was observed across key subgroups, including patients younger than 65 years and those 65 years or older, as well as in both the PD-L1 tumor proportion score [TPS] less than 1% and 1% or greater populations, suggesting potential broad applicability rather than limitation to a biomarker-selected group. If confirmed in larger randomized trials, this approach could shift frontline practice toward earlier use of PD-1/VEGF bispecifics with chemotherapy, potentially establishing a new standard backbone.

For clinicians who are navigating emerging data across RC148, ivonescimab, and pumitamig in the same class of mechanism, are there meaningful differences in how RC148 is engineered or how it behaves that you would expect to translate into different clinical results?

Yes, there are several meaningful differences in the design of RC148 compared with other PD-1/VEGF bispecifics in development. First, the anti–PD-1 backbone is derived from the sequence of an established PD-1 inhibitor, providing strong immune checkpoint blockade. Second, the anti-VEGF portion is a nanobody with a smaller molecular weight and a unique sequence, which may confer better tumor penetration and stability. In addition, RC148 incorporates a silenced Fc effector function, designed to [eliminate] antibody-dependent cellular cytotoxicity and antibody-dependent cellular phagocytosis to reduce potential immune-related adverse effects. We have seen promising early efficacy and a favorable safety profile in the RC148-C002 study.

What did the safety profile look like in practice, and were there any signals that would change how you would select or monitor patients, particularly with squamous histology?

The most common treatment-related adverse events were hematologic toxicities, which are expected with a chemotherapy-containing regimen. Immune-related adverse events and VEGF-related toxicities were mostly low grade, with a low incidence of grade 3 or higher events. In patients with squamous histology, no high-grade bleeding events were observed at the selected dose.

We would exclude only patients with clear high-risk features for hemorrhage, such as major blood vessel invasion or large necrotic cavities. Routine monitoring of blood pressure and urine protein remains appropriate, and the safety profile supports continued evaluation in squamous NSCLC with appropriate patient selection.

Is there a patient subgroup where the benefit was most pronounced, and do you see a role for biomarker selection with this class?

As mentioned, benefit was observed broadly across key subgroups, including patients younger than 65 years and those 65 years or older, as well as in both the PD-L1 TPS less than 1% and 1% or greater populations. Notably, even patients with PD-L1–negative tumors appeared to derive benefit, which is an important signal. This suggests the combination may be suitable for a broad first-line NSCLC population. While we continue to explore whether certain biomarkers may enrich for greater benefit, the current data support a broad-population approach rather than narrowing to a selected subgroup.

How confident are you that these results will hold in a global population, and what would you want to see from the next phase of development to answer that question?

We are very encouraged by the data we have seen so far. Although this study enrolled a Chinese population, the dose-optimization design, adequate sample size, and the totality of the data generated have been endorsed by the FDA, which has authorized the initiation of a global phase 3 trial sponsored by AbbVie. Importantly, the PD-1/VEGF bispecific class has already demonstrated clinical benefit in both Eastern and Western populations, supporting the generalizability of this approach.

The ongoing phase 3 programs in China and globally will provide definitive confirmation, but the current evidence gives us strong confidence in broad translatability.

References

1. Zhang L, Zhao Y, Fan Y, et al. RC148 (ABBV-1480, PD-1/VEGF bispecific antibody) plus chemotherapy in first-line locally advanced or metastatic non-small-cell lung cancer. Presented at: IASLC 2026 World Conference on Lung Cancer; September 12-15, 2026; Seoul, South Korea. Abstract OA14.01.03.

2. AbbVie to present new data at WCLC 2026 showcasing innovation across lung cancer pipeline. News release. AbbVie. August 21, 2026. Accessed September 15, 2026. https://news.abbvie.com/2026-08-21-AbbVie-to-Present-New-Data-at-WCLC-2026-Showcasing-Innovation-Across-Lung-Cancer-Pipeline

3. HARMONi-6 Shows OS Benefit With Ivonescimab/Chemo Over Tislelizumab/Chemo in First-Line Squamous NSCLC. OncLive. Published May 31, 2026. Accessed September 15, 2026. https://www.onclive.com/view/harmoni-6-shows-os-benefit-with-ivonescimab-chemo-over-tislelizumab-chemo-in-first-line-squamous-nsclc

4. Pumitamig Plus Chemo Demonstrates Encouraging Efficacy in Frontline NSCLC. OncLive. Published June 16, 2026. Accessed September 15, 2026. https://www.onclive.com/view/pumitamig-plus-chemo-demonstrates-encouraging-efficacy-in-frontline-nsclc