As the race to develop oncology bispecifics heats up, Pfizer has offered a first look at its strategy to dethrone Keytruda and establish its newly acquired PD-1xVEGF drug as a new cornerstone of cancer immunotherapy.
The New York pharma on Monday unveiled seven near-term trials of its PD-1xVEGF bispecific antibody, the first of what chief oncology officer Jeff Legos, Ph.D., called “many planned waves” of clinical investigation into PF-08634404, also known as SSGJ-707, in various cancer types.
“We believe that ’4404 is a foundational asset and a strong, seamless fit with Pfizer’s oncology strategy,” Legos said on a Nov. 10 investor call, the second of its kind focused on the bispecific in less than four months after Pfizer closed its potential $6 billion deal with the drug’s original developer, China’s 3SBio, in late July.
“We are laser-focused on developing ’4404 with speed, with breadth and depth,” he added.
Two global phase 3 trials have already been registered with ClinicalTrials.gov. These include a high-stakes head-to-head study against Merck & Co.’s PD-1 king Keytruda in first-line non-small cell lung cancer. The study, which will enroll 1,500 patients across nonsquamous and squamous subtypes, will pit PF-08634404 and chemotherapy against Keytruda-chemo regimens, which are the current standard of care. The dual primary endpoints of the study are progression-free survival and overall survival, according to Legos.
The launch of this trial unavoidably puts Pfizer/3SBio on a collision course with Summit Therapeutics/Akeso’s ivonescimab and Bristol Myers Squibb/BioNTech’s pumitamig, two other PD-(L)1xVEGF drugs in phase 3 testing in first-line NSCLC.
Pfizer built its confidence in its phase 3 approach for PF-08634404 based on results from a phase 2 trial conducted by 3SBio in China. In the study, treatment with the bispecific at 10 mg/kg and chemo yielded an overall response rate (ORR) of 58.6% in patients with nonsquamous NSCLC. Further, the ORR was 69.2% among those with squamous disease who were treated with the bispecific when the chemo partner was nab-paclitaxel and 37.5% when paclitaxel was the combo partner.
The ORR for the squamous population was calculated after a “considerably shorter” follow-up period, Legos noted. The results were presented at the Society for Immunotherapy of Cancer 2025 annual meeting during this past weekend.
By comparison, in the same study, a combination of BeOne Medicines’ PD-1 inhibitor Tevimbra and chemo yielded a 38.7% ORR in nonsquamous patients and 28.6% in squamous participants.
Grade 3 or above treatment-related adverse events occurred in 39% of patients receiving the 3SBio bispecific at 10 mg/kg and 32.8% receiving Tevimbra.
Summit/Akeso’s first-in-class PD-1xVEGF bispecific ivonescimab has already reported phase 3 data—albeit from a China-only study—in combination with chemo in patients with untreated NSCLC. In the phase 3 HARMONi-6 trial, which enrolled patients with first-line squamous NSCLC, ivonescimab and chemo reduced patients’ risk of progression or death by 40% compared with Tevimbra and chemo, according to results presented last month at the 2025 European Society for Medical Oncology Congress.
The ORR was 75.9% for the ivonescimab arm in that trial. On Monday’s call, Pfizer’s PF-08634404 franchise lead, Arati Rao, M.D., described the two bispecific drugs’ ORR numbers as very similar, considering the Pfizer trial’s small size and short follow-up time. Pfizer expects similar results as it expands into a larger study, Rao explained.
But as Citi analyst Geoff Meacham noted on the call, the all-important first-line NSCLC field is getting crowded with next-generation candidates. That’s why Pfizer hopes that after establishing PF-08634404’s profile alongside the existing standard of care, “the next wave of innovation will move into novel combinations,” Legos said.
One of Pfizer’s planned phase 1/2 studies will see the company combine PF-08634404 with its antibody-drug conjugates in NSCLC.
The second phase 3 trial for PF-08634404 will again see Pfizer eying similar territory as rivals Summit/Akeso and BioNTech/BMS. Pfizer’s planned 800-subject study will evaluate PF-08634404 and chemo against bevacizumab and chemo in patients with first-line metastatic colorectal cancer that’s not BRAF-mutated or microsatellite instability-high. Again, plans are underway to evaluate the two other rival PD-(L)1xVEGF drugs in phase 3 trials in the same setting.
If the NSCLC trial can be viewed as Pfizer’s attempt to prove PF-08634404 as a better immunotherapy than Keytruda, then the mCRC study is designed to showcase the drug as a better anti-angiogenic agent than bevacizumab. But rather than having industry watchers read between the lines, Legos made it perfectly clear: “We’re aiming to make ’4404 a key part of our future oncology arsenal by displacing the current standard of care PD-1 and PD-L1 and VEGF agents with a new PD-1xVEGF bispecific backbone therapy across multiple tumor types.”
Beyond those two studies, Pfizer is planning a phase 2/3 in front-line extensive-stage small cell lung cancer, a field where BioNTech and BMS seem to be leading with their global Rosetta-Lung01 trial. In Pfizer’s planned study, the primary endpoint of the phase 3 portion will be overall survival.
There’s an unsubstantiated perception within the oncology community that existing PD-1 inhibitors aren’t that different from one another, and that Keytruda became king with the most successful clinical results because of subtleties related to patient selection and enrollment. As the competition now extends to the PD-(L1)xVEGF class, the question naturally arises whether Pfizer can leverage such an advantage for its agent, TD Cowen analyst Steve Scala asked on Monday’s call.
Legos argued that Pfizer’s expertise in cancer drug development, including an established clinical trial footprint and relationships with investigators, will help the company in its clinical endeavors. Pfizer has identified more than 500 clinical centers it has worked with in previous studies that have confirmed their willingness to participate in PF-08634404’s phase 3 trials, Legos said.
“We believe that we will be able to reach and target patients that are truly representative of those which we are seeking an indication in, including both the United States, Europe and Asia,” he said.
Pfizer’s three remaining studies with near-term starts are phase 1/2 trials in liver cancer, bladder cancer and kidney cancer.
“These seven anticipated near-term study starts are only the beginning of our plans for ’4404,” Legos said. “We’re actively working through a second wave of potential development opportunities that could deal trial starts for another 10 additional indications and 10 or more novel combinations before the end of 2026, which is a good segue to how we’re thinking about our depth of development across settings, across lines of therapies, including novel combinations.”