Innovative Therapies Across Four Key Themes Highlighted at 2022 AACR Annual Meeting

According to the information on the AACR official website, the innovative therapies selected for the Clinical Trials Plenary Session mainly focus on four themes: therapies targeting DNA damage response and KRAS,Cellular Immunotherapy,Neoadjuvant and Perioperative Immunotherapy, Combination Immunotherapy.

Therapies Targeting DNA Damage Response and KRAS

AstraZeneca/MSD: Olaparib

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, harboring 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 35 patients, with 31 evaluable. 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, showing an overall response rate of 20.8%, a disease control rate of 66.6%, a progression-free survival rate at 10 weeks of 61.5%, and a median progression-free survival of 5.1 months.

Amgen: Sotorasib

Sotorasib is a KRAS G12C covalent inhibitor developed by Amgen. In May last year, it received accelerated FDA approval for the treatment of non-small cell lung cancer (NSCLC) patients with KRAS G12C mutations. 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 KRAS G12C mutations.

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 NSCLC patients with KRAS p.G12C mutations.

Cellular Immunotherapy

BioNTech: BNT211

BNT211 comprises two products: one is a chimeric antigen receptor (CAR)-T cell candidate product targeting the tumor-specific antigen Claudin 6 (CLDN6), and the other is a CAR-T cell amplification RNA vaccine (CARVac). At this year’s AACR conference, researchers presented results from a first-in-human, open-label, multi-center, 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.

The study results showed that CLDN6 CAR-T cells ± CARVac demonstrated 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 out of 6 patients with partial response exhibited deepened responses.

Affimed: AFM13

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 cells, 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 results from a single-center phase 1/2 trial conducted in patients with refractory/recurrent CD30+ lymphoma.

Study Shows Cord Blood-Derived Natural Killer Cell Therapy Combined with AFM13 Demonstrates Good Tolerability and Antitumor Activity in Patients with Refractory/Relapsed CD30+ Lymphoma. All 13 patients receiving the recommended phase 2 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.

Neoadjuvant and Perioperative Immunotherapy

Merck: Pembrolizumab

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 sequential adjuvant therapy with pembrolizumab for the perioperative treatment of resectable gastric cancer/esophagogastric junction adenocarcinoma. The primary endpoint is the pathological complete response (pCR) rate, with secondary endpoints including 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

Durvalumab is an anti-PD-L1 antibody, and its indication is non-small cell lung cancer (NSCLC). Studies have shown that the use of anti-PD-1/L1 antibodies in neoadjuvant therapy may provide clinical benefits for patients with resectable early-stage NSCLC. At this conference, researchers presented data from a randomized Phase II 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 patients with early-stage NSCLC.

Combination Immunotherapy

AstraZeneca: MEDI5752

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 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 while reducing 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.

The study results showed that, in the Phase 1 clinical trial, MEDI5752 demonstrated promising anti-cancer activity with durable clinical benefit in patients with advanced solid tumors who were ineligible 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 indicated that MEDI5752 strongly blocked PD-1 and CTLA-4 signaling pathways and showed the potential to expand existing or new T-cell clones.

Highlight Therapeutics/MSD: BO-112 + Pembrolizumab

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 BO-112 injection 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 the Primary Efficacy Endpoint. Among 40 evaluable patients, 10 patients achieved remission (25%), including 3 complete remissions and 7 partial remissions. 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.

Editor: Qijin

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