Abstract
Preliminary data from a phase I trial of MEDI5752, a bispecific antibody targeting both PD-1 and CTLA4, indicate the drug is well tolerated and active, with durable responses seen across diverse tumor types.
According to a first-in-human evaluation of MEDI5752 (AstraZeneca), the bispecific antibody targeting both PD-1 and CTLA4 has a reasonable toxicity profile and shows signs of efficacy, with durable responses seen across diverse tumor types. Preliminary data from the ongoing trial were presented during the American Association for Cancer Research Annual Meeting 2022 in New Orleans, LA, April 8–13.
“The success of anti–PD-1 therapies has overshadowed that of anti-CTLA4 agents,” remarked lead investigator Ben Tran, MBBS, of Peter MacCallum Cancer Centre in Melbourne, Australia. A key issue with ipilimumab (Yervoy; Bristol Myers Squibb) is that “we know its activity is only modest and higher doses, although more effective, haven't been widely adopted in the clinic due to increased grade 3–4 immune-related adverse events.”
More generally, “we still have much to learn about CTLA4 blockade, particularly in mouse versus man,” observed study discussant Jason Luke, MD, of the University of Pittsburgh in Pennsylvania. Ipilimumab generates antitumor effects in mice by depleting their immunosuppressive regulatory T cells (Treg). However, “it's really important to know that this is not the case in humans,” he said. “The exact mechanism could be through T-cell priming or reinvigoration in the tumor microenvironment—but to be clear, it's not through Treg depletion.”
MEDI5752 was developed “to address the challenge of delivering greater CTLA4 inhibition without adding toxicity,” Tran said. It preferentially targets CTLA4 on T cells that also express PD-1, using the latter “as an anchor to enhance CTLA4 blockade in the immediate vicinity,” he explained. Compared with a combination of conventional PD-1 and CTLA4 antibodies, it's better at stimulating CD4+ T-cell proliferation, accumulating in tumors, and it shows greater efficacy in vivo (Cancer Discov 2021;11:1100–17).
Tran reported findings on 86 patients treated with MEDI5752 so far. Most had renal cell carcinoma (RCC) and non–small cell lung cancer (NSCLC); other tumor types represented included head and neck squamous cell carcinoma and mesothelioma. The objective response rate was 19.8%, including one complete response in a patient with Merkel cell carcinoma. Among 63 evaluable patients, the molecular response rate—decreases in circulating tumor DNA of 50% or higher within the first 6 weeks of therapy—was 36.5%. Responses were durable, Tran said; the median was 17.5 months, and he highlighted a patient with gastric cancer who maintained a partial response for more than 2 years.
Toxicity-wise, the most common side effects were dermatitis and elevated liver enzymes. Diarrhea and colitis “occurred less than typically expected with conventional CTLA4 blockade,” Tran said. The maximum tolerated dose was not reached, “but we saw that adverse events were much less common at doses below 1500 mg,” he added, “so we're now exploring MEDI5752 at 500 mg and 750 mg in expansion cohorts” of RCC and NSCLC, respectively.
Luke noted that besides MEDI5752, several other PD-1/CTLA4 bispecifics are emerging contenders in the field. These include lorigerlimab (MacroGenics), cadonilimab (Akeso), vudalimab (Xencor), and KN046 (Alphamab Oncology). Down the road, too, “next-generation CTLA4 antibodies are coming that have been specifically designed to deplete Tregs,” he said—some in prodrug formulations that are preferentially active in the tumor microenvironment, not system-wide.
Meanwhile, “this class of bispecifics could help with unmet needs” in metastatic castration-resistant prostate cancer and ovarian cancer, Luke added. In trials, responses have been seen with ipilimumab and nivolumab (Opdivo; Bristol Myers Squibb), but high toxicity rates “have made the combination unattractive to these patient populations.” As such, if MEDI5752 and others “can thread the toxicity-versus-efficacy needle, I think there may be a development path for bispecifics as monotherapy here.” –Alissa Poh
For more news on cancer research, visit Cancer Discovery online at http://cancerdiscovery.aacrjournals.org/CDNews.
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