ASCO 2022: Emerging Targets Signal a New Direction for Indigenous Innovation — Insights from Akeso, Junshi, and Innovent

Recently, the 2022 American Society of Clinical Oncology (ASCO) Annual Meeting commenced in Chicago, USA. According to statistics from the ASCO official website abstracts and press releases from various companies, at the 2022 ASCO conference, more than 50 pharmaceutical companies in China had nearly 240 research projects accepted, with 19 projects selected for oral presentation at the 2022 ASCO conference, fully demonstrating the high value of domestic drug research in China and its recognition in the international academic community.

Today, let us take a look at the innovative projects presented at the 2022 ASCO, compare them with the international frontier, and focus on the latest research from China's innovative pharmaceutical companies.

Image Source: ASCO Official Website

Key Data Released, Dual-Antibody Showdown Imminent

At this year's ASCO Annual Meeting, a variety of novel treatment modalities are unveiling the latest clinical research findings. Significant advancements in bispecific antibodies, ADCs, cell therapies, and small molecule inhibitors are indicative of the latest trends in global drug development.

Among them, the competition in the bispecific antibody track is particularly evident, with the research results of PD-(L)1×CTLA-4 bispecific antibodies being the most impressive.

AK104, developed by Akeso Biopharma, is currently the most advanced bispecific antibody based on immune checkpoint inhibitors. At the 2022 ASCO Annual Meeting, Akeso Biopharma presented Phase 2 clinical data (NCT04868708) on AK104 combined with standard first-line therapy for the treatment of persistent, recurrent, or metastatic cervical cancer (R/MCC). The study results showed that the combination of AK104 and the standard treatment regimen demonstrated favorable anti-tumor activity and good tolerability in patients with R/MCC.

KN046, a bispecific antibody targeting PD-1/PD-L1 and CTLA-4 developed by Alphamab Oncology, has attracted significant attention for its related research. At this year's ASCO Annual Meeting, the phase 2 study results of KN046 in hepatocellular carcinoma (HCC) (NCT04542837) were reported. The findings showed that as a first-line treatment for patients with advanced unresectable or metastatic HCC, the combination of KN046 and lenvatinib demonstrated favorable outcomes in terms of ORR and PFS, with manageable safety. These results provide evidence supporting KN046 combined with lenvatinib as a potential new treatment option for such patients.

Qilu Pharmaceutical Disclosed Data on QL1706 Therapy at the ASCO Meeting. QL1706 is not strictly a bispecific antibody but a combination therapy of PD-1 and CTLA-4 (PD-1 IgG4 + CTLA-4 IgG1), developed using Qilu's MabPair combination antibody technology platform. The disclosed data pertains to the efficacy and safety of QL1706 in advanced nasopharyngeal carcinoma: pooled cohort results from a Phase 1a/1b trial.

In addition to the aforementioned bispecific antibodies, in the PD-L1/TGF-β bispecific antibody field, Hengrui Medicine and Promab Biotechnologies have respectively released early clinical data for SHR-1701 and PM8001. In the HER2×HER2 bispecific antibody field, BeiGene and Alphamab Oncology have respectively disclosed early clinical data for Zanidatamab and KN026. Additionally, Akeso Biopharma has released two sets of early clinical data for the PD-1/VEGF bispecific antibody AK112, while Innovent Biologics announced data for the CD137/PD-1 bispecific antibody IBI319.

Not Only Gastric Cancer, ADC Explores New Directions

At this year's ASCO Annual Meeting, domestic companies in the ADC field continue to focus on the HER2 domain, with participating companies including Rongchang Bio, Lepu Bio, and Kelun Pharmaceuticals. However, in terms of indications, new directions have begun to be explored, primarily reporting on urothelial carcinoma (UC) and breast cancer.

Rongchang Pharmaceutical: Urothelial Carcinoma

RemeGen's Disitamab Vedotin Successfully Approved for Gastric Cancer Treatment Indication on June 9, 2021, Becoming China’s First Domestically Developed ADC to Reach the Market. Just Half a Year Later, on January 6, 2022, Disitamab Vedotin Received NMPA Approval for Its Second Indication, Used for Treating Locally Advanced or Metastatic UC with HER2 Expression, Bringing an Entirely New Change to Clinical Diagnosis and Treatment.

At the 2022 ASCO Annual Meeting, three clinical studies on Vidic妥单抗 were selected for inclusion in this year's poster discussion session, and at the same time, they formed a special discussion on the treatment of urothelial carcinoma with Vidic妥单抗. These are: 1) Preliminary results of a phase 1b/2 combination study of Vidic妥单抗 and Toripalimab联合治疗局部晚期或转移性尿路上皮癌; 2) Phase 2 clinical study of Vidic妥单抗 in HER2-negative (IHC test results are 0 or 1+) locally advanced or metastatic urothelial carcinoma; 3) Comprehensive analysis of clinical trials C005 and C009 of Vidic妥单抗 in treating HER2-overexpressing (IHC test results are 2+ or 3+) metastatic urothelial carcinoma.

In addition, the new pan-cancer treatment model of Disitamab Vedotin also debuted at this conference, namely the preliminary results of the study on Disitamab Vedotin combined with radiotherapy and immunotherapy for HER2-expressing advanced refractory solid tumors (PRAEG3.0 study) were announced for the first time.

Lepu Biopharma: Urothelial Carcinoma

In addition, Lepu Biopharma announced the research results of MRG-002 in UC indications at this year's ASCO Annual Meeting. In a single-arm, multi-center Phase II study, the preliminary results of MRG002 showed that it had certain efficacy in treated HER-2 positive unresectable locally advanced or metastatic UC patients, with controllable safety; further evaluation is ongoing.

Kelon Pharmaceutical: Breast Cancer

Kelon Pharmaceutical Actively Explores the Treatment Prospects of HER2 ADC in Breast Cancer. A166 is a HER2-targeted ADC drug that conjugates a novel toxin molecule (Duo-5, a tubulin inhibitor) to a HER2 antibody (trastuzumab) via a protease-cleavable linker. Phase 1 clinical research data of A166 was selected for presentation as a poster at the 2022 ASCO Annual Meeting. The trial conclusions showed that the previously demonstrated clinical benefits and safety profile of A166 remained consistent. In heavily pretreated patients with HER2-positive metastatic breast cancer, A166 demonstrated manageable toxicity and promising anti-tumor activity.

Huadong Medicine: Ovarian Cancer

At this year's ASCO Annual Meeting, Huadong Medicine will present the results of a Phase 2 trial of its folate receptor (FRα) ADC drug Mirvetuximab Soravtansine (IMGN853) in FRα-high recurrent ovarian cancer. In this open-label, multicenter clinical study (NCT04274426), the ORR was 71% among 17 patients, with a median PFS of 15 months, and the ORR reached 80% in the subgroup with high FRα expression. The therapy has already submitted a BLA to the FDA and was recently granted Priority Review, positioning it to potentially become the 15th ADC drug approved globally.

Breaking the Internal Struggle, Cell Therapy Advances on Solid Tumors

After years of development, cell therapy has become one of the hottest fields in cancer research. Its achievements in the treatment of blood tumors have been particularly encouraging, giving many cancer patients hope for a "cure." In the abstracts released at this year's ASCO conference, we have seen that major local biotech pharmaceutical companies in China are also making significant progress in solid tumors, becoming another powerful weapon to conquer cancer.

Original Biotech: Multiple Myeloma

Original Biotech announced the results of the first-in-human Phase 1 study of its GPRC5D CAR-T therapy, OriCAR-017, in patients with relapsed/refractory multiple myeloma. The study results showed that OriCAR-017 demonstrated good safety and significant efficacy in multiple myeloma patients. Most AEs were temporary and manageable, with 100% ORR and 100% MRD negativity rate, along with favorable safety, supporting OriCAR-017 as a competitive treatment option. Notably, patients who had relapsed after prior BCMA CAR-T therapy could still benefit from OriCAR-017.

Gracell Biotechnologies: Multiple Myeloma

GC012F is a BCMA/CD19 dual-target CAR-T product. The latest data shows that the therapy achieves a complete response rate of nearly 100%. This candidate product is based on Gracell Biotechnologies' proprietary FasTCAR platform technology, which has the advantage of "production completed in one day." In November 2021, it was granted orphan drug designation by the U.S. FDA for the treatment of multiple myeloma.

At this year's ASCO meeting, Gracell Biotechnologies presented updated results from a multicenter, first-in-human study evaluating the BCMA/CD19 dual-targeting autologous CAR-T cell therapy GC012F in patients with relapsed/refractory multiple myeloma. The results showed that: as of January 26, 2022, 28 patients were assessed for efficacy, with a median follow-up time of 6.3 months (range 1.8-29.9 months); currently, the study is still conducting ongoing follow-ups with patients to evaluate the depth of response.

Sidansai: Colorectal Cancer

Based on its self-developed CoupledCAR® platform technology, Stancells has constructed the GCC19CART, a CAR-T cell therapy targeting GUCY2C for the treatment of patients with relapsed/refractory colorectal cancer (R/RmCRC). In August 2021, it received clinical trial approval from the U.S. FDA and was granted Fast Track designation by the FDA in April 2022.

At this ASCO meeting, Sidansai will report data from 21 subjects enrolled in two dose-escalation cohorts of the GCC19CART China IRB clinical trial. As of May 3, 2022, 13 subjects were enrolled in the Level 1 dose group (1x10^6 cells/kg), and 8 subjects were enrolled in the Level 2 dose group (2x10^6 cells/kg). The overall objective response rate (ORR) at both dose levels was 28.6%; the disease control rate (DCR, i.e., the tumor volume did not increase after using the drug) within 3 months was 100%.

CARsgen Pharma: Gastric Cancer

CARsgen Pharma developed the world's first CAR-T cell therapy targeting Claudin18.2—CT041. In May this year, the interim results of the latest Phase 1 trial of CT041 were published online in *Nature Medicine*. The results showed that CT041 demonstrated significant efficacy and excellent tolerability, marking a breakthrough by a Chinese team in overcoming the bottleneck of CAR-T therapy in solid tumors.

At this year's ASCO meeting, CARsgen Therapeutics will further present the Phase 1b/2 study results of CT041 in treating advanced gastric cancer/gastroesophageal junction adenocarcinoma and the Phase 1b data for pancreatic cancer. Notably, the patients enrolled in the clinical trial are "advanced gastric cancer/gastroesophageal junction adenocarcinoma (GC/GEJ) with positive Claudin18.2 expression who have failed at least two prior lines of therapy," representing a difficult-to-treat advanced patient population.

Xiangxue Pharmaceutical: Soft Tissue Sarcoma

Xiangxue Pharmaceutical Possesses High-Affinity TCR-T Technology and Has Developed the TCR-T Cell Therapy Product TAEST16001 Based on This Technology. Its Phase 1 Clinical Trial Was Selected for Oral Presentation at This Year's ASCO Meeting. The Clinical Trial Is an Open-Label, Single-Arm, Dose-Escalation and Expansion Study Designed to Evaluate the Safety, Tolerability, PK, PD, and Preliminary Efficacy of TAEST16001 in Patients with Soft Tissue Sarcoma. Results Showed That Among 12 Efficacy-Evaluable Patients, 5 Had Partial Responses, 5 Had Stable Disease, and 2 Had Disease Progression, with an Overall Response Rate of 41.7%. Overall, TAEST16001 Demonstrated Acceptable Tolerability, Supporting Further Expansion Studies of This Product in Advanced Soft Tissue Sarcoma.

Emerging Immune Targets Mark New Directions

In recent years, the "internal competition" surrounding PD-1 and PD-L1 has come to an end, while other emerging tumor immunotherapy targets have become the "new frontier." At this year's ASCO Annual Meeting, we found that biotech companies in China have updated the latest clinical data on new targets such as BTLA, LAG-3, and CD73.

Junshi Biosciences: BTLA

B and T Lymphocyte Attenuator (BTLA), as an immune checkpoint molecule, shares a similar structure and intracellular signaling mechanism with other immune checkpoint molecules such as PD-1 and CTLA-4. It is expressed not only on the surface of T cells but also on B cells, NKT cells, and dendritic cells. By binding to its ligand, it transmits inhibitory signals and plays a negative regulatory role in the body's immune modulation.

At the 2022 ASCO Annual Meeting, Junshi Biosciences presented the Phase 1a dose-escalation study results of its self-developed recombinant humanized IgG4 monoclonal antibody targeting BTLA, Icatolimab (TAB004/JS004), as a monotherapy for patients with advanced solid tumors, as well as the Phase 1 study results of Icatolimab as a monotherapy or in combination with Toripalimab for the treatment of relapsed/refractory lymphoma. The study results showed that: Icatolimab monotherapy was well tolerated at all evaluated doses and demonstrated preliminary clinical efficacy as a single agent. The combination of Icatolimab and Toripalimab (anti-PD-1) for the treatment of patients with advanced solid tumors is currently ongoing. Icatolimab alone or in combination with Toripalimab was well tolerated at all evaluated doses and showed preliminary clinical efficacy in patients with relapsed/refractory lymphoma.

Innovent Biologics: LAG-3

IBI110 is a recombinant fully human anti-LAG-3 monoclonal antibody developed by Innovent Biologics. Following the initial release of IBI110’s Phase 1a/1b clinical data at last year's ASCO, Innovent presented updated data at this year's ASCO Annual Meeting, along with preliminary Phase 1b clinical data in two cancer types: gastric and gastroesophageal junction cancer, and squamous non-small cell lung cancer. The trial conclusions indicate that IBI110, as a monotherapy or in combination with sintilimab, demonstrated acceptable safety and promising antitumor activity.

Weili Zhibo: LAG-3

LBL-007 is a fully human IgG4 subtype monoclonal antibody independently developed by VibeBio. At this year's ASCO Annual Meeting, VibeBio announced the Phase 1 clinical results of LBL-007 in combination with Junshi Biosciences' PD-1 antibody Toripalimab for the treatment of unresectable or metastatic melanoma. The disclosed abstract data showed that the combination of LBL-007 and Toripalimab demonstrated good tolerability and promising efficacy in patients with unresectable or metastatic melanoma, particularly in acral melanoma patients who had not received anti-PD-(L)1 therapy.

I-Mab: CD73

At the 2022 ASCO Annual Meeting, I-Mab announced positive Phase 2 clinical data for the combination of CD73 antibody uliledlimab and toripalimab in the treatment of non-small cell lung cancer (NSCLC), with a Phase 3 clinical study expected to commence in 2023.

Data Show: Monotherapy or Combination Therapy with Youlaili Monoclonal Antibody Demonstrates Good Safety and Tolerability, with No Dose-Limiting Toxicity (DLT) Events Observed. Positive efficacy signals were observed in a group of advanced NSCLC patients unsuitable for standard treatment. Clinical data confirm that the therapeutic response is highly correlated with CD73 expression in tumors, further suggesting CD73 as a predictive biomarker. In addition, I-Mab Biopharma announced the latest Phase 2 clinical study data as of March 29, 2022. The latest data show that positive efficacy signals were observed in a cohort of advanced NSCLC patients (mostly in stage four lung cancer) unsuitable for standard treatment among three groups with different treatment situations.

Inspiration

In recent years, capital has flooded in under policy stimulus, and China has ushered in a major innovation boom. With a favorable policy environment and capital-driven support, the rise of innovation in China is accelerating. Domestically produced innovative drugs are gradually entering the harvest period, and in the coming years, more significant innovative products will be approved for marketing in China. However, it cannot be ignored that the window of opportunity for "generalized innovation" is becoming shorter, medical insurance cost control is tightening, and competition in the field is increasingly fierce. The industry is slowly moving into an era of "selective premium innovation." Homogeneous competition will continue to intensify, and homogeneous products will gradually lose their competitiveness. In contrast, new technologies, scarce technology platforms, differentiated therapeutic areas, and innovative drug delivery methods could provide companies with better competitive advantages. Companies with deep technological expertise are expected to stand out.

Editor: Sanqi

Disclaimer: The views expressed in this article are solely those of the author and do not represent the position of PharmNet. We welcome exchanges and additional insights in the comment section; for reprints, please be sure to credit the author and source of the article.