The VEGF/PD-L1–directed bispecific antibody pumitamig (BNT327/BMS986545) has been shown to restore immune activity and improve outcomes in patients with metastatic triple-negative breast cancer (TNBC), showing strong response rates even in patients with a PD-L1 combined positive score (CPS) lower than 10, according to Sarah Sammons, MD.
Previously, data from a phase 1b/2 trial (NCT05918133) conducted in China and presented at the 2024 San Antonio Breast Cancer Symposium (SABCS) showed that at a median follow-up of 19.5 months (95% CI, 18.0-20.6), patients with previously untreated, locally advanced or metastatic TNBC who received pumitamig plus nab-paclitaxel (Abraxane), regardless of PD-L1 CPS (n = 42), achieved an overall response rate (ORR) of 78.6% (95% CI, 63.2%-89.7%), including a complete response rate of 2.4% and a partial response rate of 76.2%.1
These positive findings prompted the global phase 2 investigation (NCT06449222) of pumitamig in combination with chemotherapy in patients with first- and second-line advanced TNBC.2 In this trial, patients in cohort 1 received pumitamig at 1 of 2 dose levels in combination with nab-paclitaxel. In cohort 2, patients received pumitamig at varying dose levels in combination with paclitaxel, gemcitabine plus carboplatin, or eribulin. Efficacy data from evaluable patients in cohort 1 (n = 39), which were presented at the 2025 SABCS, showed an unconfirmed ORR of 71.8% (95% CI, 55.1%-85.0%), a confirmed ORR (cORR) of 61.5% (95% CI, 44.6%-76.6%), and a disease control rate (DCR) of 92.3% (95% CI, 79.1%-98.4%). Additionally, the safety profile was deemed manageable, and no new safety signals were reported.
“The global study validated the data we saw from China, that [pumitamig] is an active agent,” Sammons said in an interview with OncLive®.
In the interview, Sammons discussed how pumitamig’s dual-protein targets position the agent as a unique agent within the TNBC treatment arena, highlighted efficacy and safety findings from the phase 2 global trial, and explained how the TNBC treatment paradigm is evolving to shift bispecific antibodies and antibody-drug conjugates (ADCs) into the first-line settings.
Sammons is associate director of the Metastatic Breast Cancer Program and a senior physician at Dana-Farber Cancer Institute, as well as an assistant professor of medicine at Harvard Medical School, both in Boston, Massachusetts.
OncLive: What is the mechanism of action of pumitamig? What is the rationale for investigating this agent in TNBC?
Sammons: We are excited about the prospect of pumitamig in metastatic TNBC. Pumitamig is a VEGFA and PD-L1 bispecific checkpoint inhibitor, so it targets both [proteins] in one molecule. This dual mechanism of targeting is compelling because by combining immune checkpoint blockade with anti-angiogenic activity, there is synergy regarding pumitamig aiming to restore T-cell function, normalize the tumor vasculature, and enhance immune cell function to get to those immune cells within the tumor. There are also data showing that immune checkpoint inhibitor resistance is linked to VEGF upregulation, so naturally, this bispecific antibody was one we wanted to investigate in TNBC.
What is important to note about the design of the global phase 2 trial that evaluated pumitamig in patients with locally advanced or metastatic TNBC?
We had already seen pumitamig data with a taxane out of China a few years ago in first-line TNBC, and it led to an extremely high ORR. This [global phase 2 trial] presented at SABCS 2025 was the first trial [to investigate pumitamig] in an ex-China population. This was a randomized, open-label, multicohort study in patients with first- or second-line metastatic TNBC. Importantly, [enrollment was allowed] irrespective of PD-L1 status.
What was presented at SABCS 2025 was the initial evaluation of 74 patients as of the data cutoff of October 2025. Cohort 1 evaluated pumitamig at 15 mg/kg or 20 mg/kg every 2 weeks with nab-paclitaxel. Cohort 2 investigated pumitamig with multiple different chemotherapy agents: paclitaxel, gemcitabine, carboplatin, or eribulin. The rationale for combining [pumitamig] with all these different agents was to make sure it was safe with all these different chemotherapy backbones, so [investigators] could rationally plan the phase 3 trial.
What key efficacy data have been presented from the phase 2 global study of pumitamig in TNBC?
The efficacy results from cohort 1 were presented from 39 efficacy-evaluable first- or second-line patients, showing a cORR of 61.5% and an unconfirmed ORR of [71.8%]. The DCR was 92.3%. [These findings are] striking for a mixed first- or second-line population.
What was also striking here was that we are not using immunotherapy for most patients with metastatic TNBC. We’re only using it in patients who are PD-L1 positive and have never been exposed to immunotherapy in the past. Approximately two-thirds of patients are PD-L1 negative and do not have an immunotherapy option. In this study, the ORRs were identical between the PD-L1–positive and PD-L1–negative populations, showing that we have hope for an immunotherapeutic strategy for PD-L1–negative patients, who have not had [this type of treatment option] before. [However], it’s too soon to tell whether efficacy differed based on the chemotherapy backbone, because most of the patients [in the] presented [population] received a taxane.
What is the safety profile of pumitamig? Did safety outcomes vary in the phase 2 trial based on the chemotherapy backbone that was used?
[The safety profile in cohort 1] was manageable and consistent with what you would expect when you combine a PD-L1 inhibitor and a VEGF inhibitor. There did not seem to be synergistic [toxicity] activity. Grade 3 or higher treatment-related adverse effects [AEs] were seen in [42.5%] of patients. Importantly, there were no pumitamig-related deaths, and the discontinuation rate was low, at only 7.5%.
Phase 2 Global Trial of Pumitamig in Metastatic TNBC: Highlights
- Pumitamig plus nab-paclitaxel demonstrated significant efficacy in patients with first- or second-line metastatic TNBC, achieving an unconfirmed ORR of 71.8% (95% CI, 55.1%-85.0%) and a cORR of 61.5% (95% CI, 31.6%-86.1%) in cohort 1.
- Patients treated with the higher 20-mg/kg dose of pumitamig experienced deeper and more sustained circulating tumor DNA reductions than those who received the 15-mg/kg dose, with 92.9% of patients (95% CI, 66.1%-99.7%) in the 20-mg/kg group achieving a reduction of 50% or more by cycle 3.
- The combination’s safety profile was consistent with findings from prior studies and showed no new safety signals, though treatment-related AEs were frequent, occurring in 97.5% of patients in cohort 1 and 88.2% of patients in cohort 2.
We’re combining [this agent with] chemotherapy, so we’re seeing AEs from the chemotherapy and from the immunotherapy. We’re seeing similar, maybe even slightly lower, rates of immune-mediated toxicities. Regarding the VEGF-related toxicities, we haven’t used VEGF [inhibitors for breast cancer management] in the US in over a decade, given the withdrawal [of the breast cancer indication for bevacizumab (Avastin)]by the FDA [in 2011]. But, if we start using [pumitamig] in clinical practice, we will have to get used to managing high blood pressure and low-grade proteinuria.
What are the next steps for advancing pumitamig in clinical trials and potentially bringing it to the clinic?
This compound is currently in a phase 3 registrational trial. ROSETTA Breast-01 [NCT07173751] is a global, randomized trial evaluating pumitamig plus chemotherapy vs placebo plus chemotherapy in patients with first-line metastatic TNBC who are either PD-L1 negative or were previously ineligible for PD-L1 inhibitor therapy. Mostly, the PD-L1–negative population is where [research is] moving this compound.
ADCs are making their move to the frontline TNBC setting, and other bispecific antibodies are also being investigated in this arena. With all these novel classes of agents potentially affecting early lines of TNBC management, how do you see the treatment paradigm continuing to evolve as these agents potentially become available in the clinic?
The TROP2-directed ADCs are moving into the first-line setting. Given positive findings from the phase 3 ASCENT-03 [NCT05382299], ASCENT-04 [NCT05382286], and TROPION-Breast02 [NCT05374512] trials, datopotamab deruxtecan-dlnk [Datroway] and sacituzumab govitecan-hziy [Trodelvy] may be moving into the first-line PD-L1–negative population. We do not have FDA approval for either of those agents in the PD-L1–negative population at this time, and we don’t have safety data with either of those agents combined with pumitamig. Therefore, unfortunately, it wasn’t possible to bring either of those agents into the first phase 3 [trial investigating pumitamig in first-line TNBC].
However, I think of [these classes of agents] as separate [from each other]. I think of ADCs as chemotherapy, and I think of pumitamig as an immunotherapeutic strategy for a previously immunotherapy-ineligible patient. There may be room for these PD-L1– and VEGF-directed bispecific antibodies with chemotherapy. Or, in the future, we may start to see combinations with these bispecific antibodies and ADCs as well. However, to move [pumitamig] into the clinic most quickly, for now, it needs to be combined with chemotherapy in the registrational trial.
References
- Wu J, Zhang J, Tong Z, et al. Interim overall survival of patients with locally advanced or metastatic triple-negative breast cancer treated with first line PM8002/BNT327 in combination with nab-paclitaxel in phase Ib/II study. Clin Cancer Res. 2025;31(suppl 12):PS3-08. doi:10.1158/1557-3265.SABCS24-PS3-08
- Schmid P, Williams A, Aksoy S, et al. Preliminary data from a global multicohort phase2 randomized trial of pumitamig (PD-L1 × VEGF-A bsAb) + chemotherapy for 1L/2L+ locally advanced/metastatic TNBC. Clin Cancer Res. 2026;32(suppl 4):PS1-13-25. doi:10.1158/1557-3265.SABCS25-PS1-13-25
