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A new generation of checkpoint inhibitors is emerging, with some showing more promise than others. From recent TIGIT failures to high-potential targets like VEGF, BioSpace explores what’s on the horizon in immuno-oncology. Eleven years after Merck’s Keytruda transformed the treatment space for several cancers, immuno-oncology—and checkpoint inhibitors (CPI) especially—are, optimistically speaking, at a crossroads. For those who see the glass as half empty, on the other hand, the space is frustratingly stalled. “The first wave of immuno-oncology has passed us by,” Jeremy Levin, CEO of Ovid Therapeutics, told BioSpace in March. As of April 2025, the FDA had approved 14 checkpoint inhibitors, but response rates to this type of immunotherapy have plateaued at around 30% , leaving 70% of patients out in the cold. Once highly touted checkpoints, such as TIGIT, have largely failed, while CTLA-4 hasn’t yielded nearly the number of therapies as PD-1/PD-L1. There is hope, however. Bristol Myers Squibb broke through in March 2022 with the FDA approval of relatlimab (marketed in combination with Opdivo as Opdualag ), the first LAG-3-blocking antibody, and today, much of the excitement centers on ivonescimab, a PD-1/VEGF bispecific antibody being developed by Summit Therapeutics. With the overall immuno-oncology market projected to reach some $284 billion by 2033 , these companies and more are actively vying for a piece of the pie. DATA SOURCE: MERCK EARNINGS , BIOPHARMA DIVE TIGIT Trouble Companies targeting TIGIT have been riding a rollercoaster the past five years. Roche spurred excitement for this novel checkpoint in December 2021 with promising Phase II results from its anti-TIGIT tiragolumab in combination with its anti-PD-L1 Tecentriq in metastatic non-small cell lung cancer (NSCLC). It was not to last, however, as last year the combo failed to significantly improve progression-free and overall survival versus Keytruda and chemotherapy in NSCLC in a Phase II/III study. This followed similarly disappointing news from Merck, whose anti-TIGIT antibody vibostolimab, when paired with Keytruda, also failed in a Phase II NSCLC trial. The field was somewhat revived last September when iTeos Therapeutics’ anti-TIGIT belrestotug, in combination with GSK’s anti-PD-1 therapy Jemperli, bested Jemperli monotherapy in terms of confirmed objective response rate by 30% in NSCLC. Other players in this space include BeiGene, AstraZeneca, Gilead and Arcus Biosciences. VEGF in the Spotlight Many industry observers extol the value of combination therapies in immuno-oncology. One such combo generating particular attention is a PD-1/VEGF bispecific antibody being developed by Summit Therapeutics. Last September, Summit set the cancer space ablaze when it announced that ivonescimab beat Keytruda in a Phase III trial in advanced NSCLC. Ivonescimab “is really the new . . . wave of checkpoint inhibitors,” Christiana “Chris” Bardon, co-managing partner of MPM BioImpact, told BioSpace in March. Analysts cautioned, however, that the “results may or may not be generalizable beyond the China-focused patient population,” where the trial was conducted. Summit is currently running another Phase III trial in NSCLC in the U.S., with an expected primary completion date of April 2028, according to ClinicalTrials.gov . BioNTech is also a contender in this space, gaining full rights to PD-L1/VEGF-A bispecific antibody BNT327/PM8002 in the November 2024 acquisition of partner Biotheus. How will AI further the development of novel checkpoint inhibitors? Editor’s note: This article was originally published as a special edition of ClinicaSpace, BioSpace’ s weekly newsletter covering clinical trial results and research news, on April 21. You can subscribe here .