On September 10, 2024 Innovent Biologics, Inc. ("Innovent") (HKEX: 01801), a world-class biopharmaceutical company that develops, manufactures and commercializes high-quality medicines for the treatment of oncology, autoimmune, cardiovascular and metabolic, ophthalmology and other major diseases, reported the presentation of Phase 1 clinical data (ClinicalTrials.gov, NCT04085185) for IBI363 (first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein) in advanced non-small cell lung cancer at the 2024 World Conference on Lung Cancer (WCLC) (Press release, Innovent Biologics, SEP 10, 2024, View Source [SID1234646488]). Currently, Innovent is conducting Phase 1/2 clinical trials in China, U.S. and Australia to evaluate the safety, tolerability and efficacy of IBI363 in subjects with advanced solid tumors.

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First-in-class PD-1/IL-2α-bias bispecific antibody IBI363 in patients with advanced non-small cell lung cancer in a Phase 1 study

This update on previously reported Phase 1 results focuses on the safety and efficacy of IBI363 in advanced non-small cell lung cancer (NSCLC). As of the follow-up data cutoff date of August 2, 2024, 134 patients were enrolled and received IBI363 monotherapy (up to 3 mg/kg Q3W), with 95.5% having received prior PD-(L)1 immunotherapy. The median duration of IBI363 exposure was 10 weeks, and 77.6% remained on treatment. In the group of 125 patients having at least one post-baseline tumor assessment, the overall ORR was 20.8% and DCR was 74.4%.
IBI363 demonstrated encouraging efficacy signals in IO-treated squamous NSCLC, with a trend toward relatively higher ORR and DCR in the 3 mg/kg Q3W group (n=29）compared to the 1/1.5 mg/kg Q2W/Q3W group (n=27) (see table below). Despite relatively short follow-up time for the 3mg/kg Q3W subgroup, among the 18 patients who had at least 12 weeks of follow-up or end of study, the ORR and DCR were 50% and 88.9%, respectively.
Patients with at least 1
tumor assessment

sqNSCLC

1/1.5 mg/kg
(N=27)

3 mg/kg
(N=29)

3 mg/kg

with at least 12 weeks of follow-up
(N=18)

Best overall response, n (%)

Partial Response (PR)

6*

10**

9***

Stable Disease (SD)

13

16

7

Progressive Disease (PD)

8

2

2

Not Evaluable (NE)

0

1

0

ORR, % (95% CI)

22.2% (8.6, 42.3)

34.5% (17.9, 54.3)

50.0% (26.0, 74.0)

DCR, % (95% CI)

70.4% (49.8, 86.2)

89.7% (72.6, 97.8)

88.9% (65.3, 98.6)

*6 patients had confirmed PR; **9 out 10 patients had confirmed PR; ***8 of 9 patients had confirmed PR.

As of the data cutoff date, for patients with squamous NSCLC who were treated with IBI363 at 1/1.5 mg/kg, the median follow up time was 7.5 months, and the median PFS was 5.5 months (95% CI, 1.5-8.3); currently, the 12-month PFS rate is 30.7%, showing a long-term benefit advantage of immunotherapy. The median PFS was not reached for subjects who received 3mg/kg Q3W.
Similar responses were observed among squamous NSCLC patients with PD-L1 TPS<1% (n=22) and TPS≥1% (n=22) treated across the 1/1.5 mg/kg and 3 mg/kg doses, with ORRs of 36.4% and 31.8% respectively, suggesting IBI363 has efficacy regardless of PD-L1 expression.
IBI363 has a manageable safety profile. The most common treatment related adverse events (TRAEs) included arthralgia, anemia, hyperthyroidism, hypothyroidism and rash. Overall, 20.1% of patients experienced TRAEs ≥ grade 3 and 6.0% experienced TRAE leading to treatment discontinuation. In the 3 mg/kg Q3W subgroup (n=57), 17.5% experienced TRAEs ≥ grade 3 and 5.3% experienced TRAEs leading to treatment discontinuation. The safety profile was consistent with the overall population. No new safety signals were identified.
Given that IBI363 has shown encouraging efficacy signals and good tolerability, this study continues to investigate the long-term efficacy and safety and to determine the RP2D in NSCLC. Additional studies are also underway to evaluate IBI363 in combination with other therapies and in other solid tumors. Relevant data and analyses will be shared in future academic conferences or publications.

Professor Jianya Zhou, The First Affiliated Hospital, School of Medicine, Zhejiang University, stated: "Lung cancer is the leading cause of cancer-related deaths globally, with non-small cell lung cancer accounting for approximately 80% of cases[1]. While PD-1/PD-L1 inhibitors have shown promising efficacy in non-small cell lung cancer, most patients eventually develop primary or secondary resistance to these immune checkpoint inhibitors. For NSCLC patients who fail IO therapy, effective treatment options are limited, with chemotherapy, such as docetaxel, achieving only about an ORR of 10% and a median PFS of under 4 months[2]. As a key cytokine that activates tumor-specific CD8+T cells, IL-2 complements immune checkpoint inhibitors in its MOA. Combining PD-1 with IL-2 may reverse the exhaustion of tumor-specific CD8+ T cells and help overcome immune resistance. As a PD-1/IL-2α-bias bispecific molecule, IBI363 has demonstrated promising antitumor activity in IO-resistant, driver gene wild-type NSCLC, with clinical benefits shown in both ORR and PFS. Additionally, its manageable safety profile, even at higher doses, provides confidence in its therapeutic potential."

Dr. Hui Zhou, Senior Vice President of Innovent, stated: "We are pleased to present the latest data on IBI363 in lung cancer at WCLC. The data highlights the promising trend of IBI363 showing better ORR and DCR at higher doses, alongside a manageable safety profile. Although the follow-up period for the 3 mg/kg dose group is still relatively short, we anticipate more mature data from longer-term follow-up and expect to see its potential as an immunotherapy for long-term survival benefits to patients. Meanwhile, in non-small cell lung cancer, particularly in IO-treated squamous NSCLC, IBI363 has demonstrated potent anti-tumor effects regardless of PD-L1 expression levels. This indicates that IBI363 could potentially offer breakthroughs in treating cold tumors with low or absent PD-L1 expression. We will continue to advance the clinical exploration of IBI363 in squamous NSCLC and other tumor types."

About IBI363 (First-in-class PD-1/IL-2α-bias bispecific antibody fusion protein)

IBI363 is a first-in-class PD-1/IL-2α-bias bispecific antibody fusion protein developed independently by Innovent Biologics. It functions by both blocking the PD-1/PD-L1 pathway and activating the IL-2 pathway. The IL-2 arm of IBI363 is designed to maintain its affinity for IL-2Rα while reducing binding to IL-2Rβ and IL-2Rγ, thereby minimizing toxicity. The PD-1 binding arm not only blocks PD-1 but also selectively delivers IL-2. This approach targets and activates tumor-specific T cells that express both PD-1 and IL-2Rα, leading to more precise and effective activation of this T cell subpopulation. IBI363 has demonstrated robust antitumor activity in various tumor-bearing pharmacological models, including those resistant to PD-1 resistance and models of metastasis. In response to urgent clinical needs, Innovent is conducting clinical studies in China, the United States and Australia to further explore the efficacy and safety of IBI363 in advanced tumors.