AACR 2022 Clinical Trials Plenary Session Highlights: 16 Innovative Therapies Across Four Key Themes

The 2022 American Association for Cancer Research (AACR) Annual Meeting is currently underway. According to information on the AACR official website, 16 studies have been selected for the Clinical Trials Plenary Session. These studies revolve around four themes: cellular immunotherapy, therapies targeting DNA damage response and KRAS, neoadjuvant and perioperative immunotherapy, and combination immunotherapy. In today’s article, let’s take a look at the key advancements of these innovative therapies based on the abstracts released by AACR.

Topic One: Cellular Immunotherapy

Stanford University, etc.: GD2-CAR T Cells

Mechanism of Action: CAR-T Product Targeting GD2 Protein

Indications: Diffuse Midline Glioma

At this conference, researchers reported the latest clinical trial results of using CAR-T products targeting the GD2 protein to treat H3K27M-mutant diffuse midline glioma. H3K27M-mutant diffuse midline glioma is a fatal central nervous system tumor that expresses high levels of disialyl ganglioside GD2. In preclinical models, intravenously administered GD2-CAR T cells (GD2-CART) led to the regression of these tumors, and locally delivered CARs exhibited enhanced activity in xenograft models of brain tumors.

Latest research results show that among 10 subjects who were adequately followed up to evaluate benefits, 9 experienced radiological or clinical benefits after intravenous infusion and subsequently received intracerebroventricular (ICV) GD2-CART infusion. Four patients continued to receive ICV infusions in the study and experienced sustained clinical and radiological benefits after enrollment, with one patient’s tumor volume nearly completely reduced (>95%) and another patient’s brainstem tumor volume almost entirely diminished (>98%).

BioNTech: BNT211

Mechanism of Action: Next-Generation CAR-T Product Targeting CLDN6

Indications: CLDN6-positive advanced solid tumors

BNT211 Contains Two Products: A Chimeric Antigen Receptor (CAR)-T Cell Candidate Targeting the Tumor-Specific Antigen Claudin 6 (CLDN6), and a CAR-T Cell Amplification RNA Vaccine (CARVac). At This Year’s AACR Conference, Researchers Presented Results from a First-in-Human, Open-Label, Multicenter, Phase 1 Clinical Trial, Aimed at Evaluating the Safety and Efficacy of CLDN6 CAR-T Cells and CARVac in Amplifying Responses in Patients with CLDN6-Positive Advanced Solid Tumors.

Study results show that CLDN6 CAR-T cells ± CARVac demonstrate acceptable safety and favorable clinical activity at the tested dose. Preliminary efficacy data at 6 weeks post-infusion in 12 evaluable patients showed an objective response rate (ORR) of 42%, including 5 patients with partial response (PR) and 6 patients with stable disease (SD); the disease control rate (DCR) was 92%. At 12 weeks, 5 of the 6 patients with partial response exhibited deepened responses.

Affimed: AFM13

Mechanism of Action: CD30/CD16A Innate Immune Cell Engager

Indications: CD30+ Lymphoma

Public information shows that AFM13 is a potential "first-in-class" innate immune cell engager (ICE). On one hand, it can bind to the CD30 antigen on the surface of lymphoma, and on the other hand, it can bind to CD16A on the surface of natural killer (NK) cells and macrophages, activating these cells without the need for co-stimulatory signals. At this conference, researchers presented the results of a single-center phase 1/2 trial conducted in patients with refractory/relapsed CD30+ lymphoma.

Study Shows Cord Blood-Derived Natural Killer Cell Therapy Combined with AFM13 in Treatment of Refractory/Relapsed CD30+ Lymphoma Patients Demonstrates Good Tolerability and Antitumor Activity. All 13 patients receiving the phase 2 recommended dose achieved a 100% objective response rate, including 6 complete responses (CR) and 7 partial responses. At a median follow-up of 6 months, progression-free survival (PFS) and overall survival (OS) across all dose levels were 58% and 79%, respectively.

Kite Corporation: axi-cel

Mechanism of Action: CD19-Targeted CAR-T Product

Indications: Large B-cell Lymphoma

Axi-cel (axicabtagene ciloleucel) is a CD19-targeted CAR-T product developed by Kite Pharma, a subsidiary of Gilead Sciences. The product was recently approved by the U.S. FDA for an expanded indication, for use as a second-line treatment for adult patients with large B-cell lymphoma (LBCL). This approval was based on positive results from the randomized, open-label clinical trial ZUMA-7. At this year’s AACR conference, researchers presented characteristics of the axi-cel product related to patient clinical outcomes from the ZUMA-7 study.

Study results show that the product characteristics of axi-cel before infusion and the pharmacokinetic (PK)/pharmacodynamic (PD) profiles after infusion are associated with subject safety and efficacy outcomes. Meanwhile, infusion products rich in naive T cells expressing CD27 and CD28 are correlated with increased event-free survival (EFS), objective response rate, and the number of complete responses. These findings could influence the evaluation of future related trials, including how enrichment of naive T cells in the product may improve treatment outcomes.

Topic Two: Therapies Targeting DNA Damage Response and KRAS

AstraZeneca/MSD: Olaparib

Mechanism of Action: PARP Inhibitor

Indications: Endometrial Cancer

Olaparib, a PARP inhibitor jointly developed by AstraZeneca and MSD, has been approved by the FDA for the treatment of various cancer types, including advanced ovarian cancer, breast cancer, and pancreatic cancer, with germline BRCA mutations. The ENDOLA study presented at this conference explores the safety and efficacy of olaparib in combination with cyclophosphamide and metformin for the treatment of patients with recurrent advanced/metastatic endometrial cancer.

According to the AACR abstract, the ENDOLA study is a Phase 1/2 open-label dose-escalation study. As of November 2019, the study enrolled a total of 35 patients, with 31 evaluable patients. The Phase 1 clinical portion determined the recommended Phase 2 trial dose of olaparib to be 300 mg twice daily (BID), and the Phase 2 clinical portion evaluated 14 patients. The overall response rate was 20.8%, the disease control rate was 66.6%, the progression-free survival rate at 10 weeks was 61.5%, and the median progression-free survival was 5.1 months.

Bayer: elimusertib

Mechanism of Action: ATR Inhibitor

Indications: Advanced Solid Tumors

Elimusertib is a selective ATR inhibitor under research by Bayer, demonstrating promising anti-tumor activity in patients with ATM-mutated advanced solid tumors. Presented at this conference were the results from the Phase 1b expansion clinical trial of the drug for treating advanced solid tumors carrying DNA damage response defects.

According to the AACR abstract, five cases of partial response assessed by RECIST criteria were observed in patients receiving elimusertib at 40 mg twice daily; in ATM IHC-deficient patients, the ORR was 9% and the DCR was 65%; in gynecological patients, the ORR was 2.3% and the DCR was 73%. The findings indicate that elimusertib monotherapy demonstrates clinical activity in patients with DNA damage response (DDR) defects, with an overall manageable safety profile, and further biomarker analyses are ongoing.

AstraZeneca: AZD5305

Mechanism of Action: PARP1 Specific Inhibitor

Indications: Breast cancer, ovarian cancer, prostate cancer, or pancreatic cancer

AZD5305 is AstraZeneca's next-generation PARP inhibitor under research, specifically designed to target PARP1. This year's AACR conference presented the results of the first human clinical trial of this drug in patients with advanced breast cancer, ovarian cancer, prostate cancer, or pancreatic cancer carrying BRCA1/2, PALB2, or RAD51C/D gene mutations.

The results showed that the candidate drug demonstrated good tolerability, with no dose-limiting toxicity observed. Among 25 evaluable patients, 7 (28%) achieved objective responses, including patients resistant to platinum-based chemotherapy and PARP inhibitors; 59% of the patients had stable disease or partial response lasting over 51 weeks; among 13 evaluable patients with circulating tumor DNA (ctDNA), 7 patients (54%) exhibited a decrease in ctDNA levels. The study results indicate that AZD5305 is a highly selective PARP1 inhibitor with favorable physicochemical properties and a broad therapeutic index, showing promising clinical activity.

Amgen: Sotorasib

Mechanism of Action: KRAS G12C Inhibitor

Indications: Non-Small Cell Lung Cancer

Sotorasib is a KRAS G12C covalent inhibitor developed by Amgen. In May last year, it received accelerated approval from the FDA for the treatment of patients with non-small cell lung cancer (NSCLC) carrying the KRAS G12C mutation. This year's AACR conference presented the two-year long-term efficacy results of the CodeBreaK 100 study on sotorasib in treating NSCLC patients with the KRAS G12C mutation.

According to the AACR abstract, the study evaluated 174 subjects who had previously received anti-PD-1/PD-L1 antibody therapy or platinum-based chemotherapy plus anti-PD-1/PD-L1 antibody therapy. The updated ORR was 40.7%, with a median DOR of 12.3 months, and median PFS and OS were 6.3 months and 12.5 months, respectively. The one-year and two-year OS rates were 50.8% and 30.3%, respectively. Additionally, sotorasib demonstrated good long-term tolerability, with mild and manageable toxicity, and no new safety signals emerged. More durable antitumor responses were observed in subjects expressing PD-L1, and the current analysis continues to support long-term clinical benefit in the subgroup of KRAS p.G12C-mutated NSCLC patients.

Topic Three: Neoadjuvant and Perioperative Immunotherapy

Merck: Pembrolizumab

Mechanism of Action: PD-1 Inhibitor

Indications: Gastric Cancer

Pembrolizumab, developed by Merck, is a PD-1 inhibitor. This study is a phase 2 trial of pembrolizumab combined with oxaliplatin and capecitabine, followed by adjuvant pembrolizumab in the perioperative treatment of resectable gastric cancer/esophagogastric junction adenocarcinoma. The primary endpoint is the pathological complete response (pCR) rate, and secondary endpoints include overall response rate, DFS, and OS.

According to the AACR abstract, as of June 17, 2021, 34 patients were evaluable for efficacy. A total of 29 patients underwent surgical resection; 7 patients achieved pCR, 6 patients approached CR, and 8 patients showed significant treatment effects in pathological evaluation. The trial met its primary endpoint, supporting further investigation of this regimen as an alternative for patients intolerant to triplet chemotherapy.

AstraZeneca: Durvalumab, Tremelimumab

Mechanism of Action: PD-L1 Inhibitor, Anti-CTLA-4 Antibody

Indications: Advanced epithelial ovarian cancer

Durvalumab is a PD-L1 inhibitor, and tremelimumab is an anti-CTLA-4 antibody. Both drugs were developed by AstraZeneca. At this conference, researchers presented the interim data of a single-arm phase 2 study named KGOG 3046. This trial aims to evaluate the efficacy and safety of combining durvalumab and tremelimumab with neoadjuvant chemotherapy for patients with advanced epithelial ovarian cancer.

Study results showed that a total of 45 patients were enrolled. After receiving neoadjuvant chemotherapy, the ORR assessed by RECIST v1.1 criteria was 86.7%. Among the patients who underwent interval debulking surgery, 30 patients achieved R0 resection, 14 patients had a CRS score of 3, and 5 patients exhibited pathological response. The most common adverse event was rash. After receiving neoadjuvant chemoimmunotherapy, significant increases were observed in stromal TIL, CD8, and the CD8/Foxp3 ratio on immunohistochemistry. Further analysis of TILs revealed a significant reduction in regulatory T cells (Tregs) within the tumor microenvironment. The study concluded that these interim data indicate that the combination of durvalumab and tremelimumab with neoadjuvant chemotherapy demonstrates clinical activity and manageable toxicity in advanced epithelial ovarian cancer.

AstraZeneca: Durvalumab

Mechanism of Action: Anti-PD-L1 Antibody

Indications: Non-Small Cell Lung Cancer (NSCLC)

Research shows that the use of anti-PD-1/L1 antibody neoadjuvant therapy may offer clinical benefits for patients with resectable early-stage NSCLC. At this conference, researchers presented data from a randomized Phase 2 study named NeoCOAST, which aimed to evaluate the effects of durvalumab used alone or in combination with anti-CD73 monoclonal antibody oleclumab, anti-NKG2A monoclonal antibody monalizumab, or anti-STAT3 antisense oligonucleotide therapy danvatirsen as neoadjuvant treatments for early-stage NSCLC patients.

Between March 2019 and September 2020, a total of 84 patients were randomly assigned to receive durvalumab, durvalumab + oleclumab, durvalumab + monalizumab, or durvalumab + danvatirsen. The major pathological response (MPR) rates for the four groups were 11.1%, 19.0%, 30.0%, and 31.3%, respectively, while the pCR rates were 3.7%, 9.5%, 10.0%, and 12.5%, respectively. The incidence of treatment-related adverse events was 34.6%, 57.1%, 50.0%, and 43.8%, respectively. MPR was more common in patients with baseline tumor PD-L1 expression ≥1% across all cohorts. The study concluded that the combination of durvalumab with the other three agents improved MPR and pCR rates compared to durvalumab alone, without new safety signals.

Bristol-Myers Squibb: Nivolumab

Mechanism of Action: PD-1 Inhibitor

Indications: Non-Small Cell Lung Cancer

Nivolumab, developed by Bristol-Myers Squibb (BMS), is a PD-1 inhibitor. The CheckMate 816 study is a randomized Phase 3 clinical trial conducted in patients with resectable non-small cell lung cancer, comparing the use of nivolumab in combination with platinum-based doublet chemotherapy as a neoadjuvant therapy versus chemotherapy alone. This study has already met its first primary endpoint, showing a statistically significant improvement in the pCR rate (24% vs 2%).

At this conference, researchers reported the interim analysis results of another study endpoint, EFS. The results showed that at a median follow-up of 29.5 months, compared with chemotherapy, nivolumab + chemotherapy significantly improved EFS in the randomized population (31.6 months vs 20.8 months), with a 2-year EFS rate of 64% (vs 45%). Combined with the pCR rate results, these analysis results support nivolumab + platinum doublet chemotherapy as a potential new treatment option for patients with resectable stage IB-IIIA NSCLC. In March this year, this combination therapy has been approved by the FDA for the treatment of resectable non-small cell lung cancer patients.

Topic Four: Combination Immunotherapy

Bristol-Myers Squibb: Ipilimumab + Nivolumab

Mechanism of Action: CTLA-4 Inhibitor, PD-1 Inhibitor

Indications: Melanoma

Ipilimumab and nivolumab are both immune checkpoint inhibitors developed by Bristol-Myers Squibb. The former is a CTLA-4 inhibitor, and the latter is a PD-1 inhibitor. At this conference, researchers are about to present a prospective randomized study comparing the combination of ipilimumab and nivolumab with ipilimumab alone in melanoma patients who did not respond to anti-PD-1 antibody treatment.

The study results showed that, with a median follow-up time of 25.3 months, the estimated 6-month PFS rates for the combination therapy group and the monotherapy group were 34% and 13%, respectively. The ORR for the combination therapy group was 28% (vs 9%), and the 12-month OS was 63% (vs 57%). Additionally, the incidence of adverse events was similar between the two groups. This data indicates that, compared to using ipilimumab alone, the combination therapy is associated with improved progression-free survival, and patients who do not respond to anti-PD-1 antibody treatment may benefit from the combination therapy with controllable toxicity.

Highlight Therapeutics/MSD: BO-112 + Pembrolizumab

Mechanism of Action: Double-stranded RNA, PD-1 Inhibitor

Indications: Melanoma

BO-112 is a synthetic double-stranded RNA developed by Highlight Therapeutics, designed to mimic the effects of viral invasion, stimulate innate immune responses, and make tumor cells more detectable by the immune system. At this conference, researchers are about to present the final results of a Phase 2 clinical study named SPOTLIGHT203. This study aims to explore the efficacy of intratumoral injection of BO-112 combined with intravenous pembrolizumab in patients with advanced melanoma who are non-responsive to anti-PD-1 antibody therapy.

Data show that the study met its primary efficacy endpoint. Of the 40 evaluable patients, 10 achieved a response (25%), including 3 complete responses and 7 partial responses. Seventeen patients had stable disease, with a disease control rate of 68%. Additionally, the safety of the combination therapy was manageable, and no participants discontinued treatment due to adverse events.

Trishula Therapeutics/AbbVie: TTX-030 + budigalimab + FOLFOX

Mechanism of Action: Anti-CD39 Antibody, Anti-PD-1 Antibody, Chemotherapy

Indications: Gastric Cancer

TTX-030 is an anti-CD39 antibody co-developed by Trishula and AbbVie, while budigalimab is an anti-PD-1 monoclonal antibody developed by AbbVie. At this year's AACR Annual Meeting, researchers are about to present the clinical trial results of TTX-030 in combination with budigalimab and FOLFOX as a first-line treatment for locally advanced or metastatic human epidermal growth factor receptor 2 (HER2)-negative gastric or gastroesophageal junction adenocarcinoma.

As of the efficacy data cutoff date, the median follow-up time was 139 days. Among 38 evaluable patients, 23 achieved a response of partial response or better, including two complete responses, while 12 patients had stable disease, resulting in an ORR of 61%. Of the 36 patients with known positive PD-L1 expression scores (CPS), response rates were 4/10 (CPS<1), 8/10 (CPS≥1 and <5), and 11/16 (CPS≥5). Preliminary results from this study indicate that TTX-030, in combination with chemotherapy and immunotherapy as a first-line treatment for locally advanced or metastatic gastric cancer, demonstrates favorable efficacy regardless of CPS status, with a manageable safety profile and no evidence of excessive toxicity. According to information on the AACR website, this marks the first clinical data report of an anti-CD39 antibody combined with chemotherapy and immunotherapy for gastric cancer.

AstraZeneca: MEDI5752

Mechanism of Action: PD-1/CTLA-4 Bispecific Antibody

Indications: Advanced Solid Tumors

MEDI5752 is a monovalent bispecific antibody developed by AstraZeneca that can simultaneously target PD-1 and CTLA-4. According to the abstract on the AACR official website, the design of this bispecific format enables MEDI5752 to preferentially inhibit these two immune checkpoint proteins on activated T cells within tumors, which may maximize tumor-specific responses and reduce peripheral toxicity. At this conference, researchers are about to present phase 1 dose escalation data from an open-label, multicenter study conducted in patients with advanced solid tumors.

Study results show that, in Phase 1 clinical trials, MEDI5752 demonstrated promising anti-cancer activity with durable clinical benefit in patients with advanced solid tumors who were unfit for standard treatment. Across different doses, the objective response rate was 19.8% and the median duration of response was 17.5 months. Additionally, analysis revealed that MEDI5752 potently blocked PD-1 and CTLA-4 signaling and showed potential to expand existing or new T-cell clones.

The annual meeting of AACR is currently underway, and we will continue to follow the relevant progress to present more cutting-edge developments from the field of cancer research at this conference.

References:

[1] AACR Conference Official Website. From https://www.abstractsonline.com/pp8/#!/10517/sessions/@sessiontype=Clinical%20Trials%20Plenary%20Session/1

*Disclaimer: This article was written by an author who has settled in Sina Medicine News. The views expressed represent the personal opinions of the author and do not reflect the position of Sina Medicine News.

▽Follow 【WuXi AppTecGermany】WeChat Official Account