Investigators Present 12 Novel Agents During 3 AACR Special Sessions

This year, investigators presented a session highlighting pipeline oncology drugs at the American Association for Cancer Research (AACR) Annual Meeting 2022, featuring first disclosures of discovery and structure of 12 novel agents, both small molecules and biologics.

The novel agents have recently entered, or will imminently enter, into phase 1 clinical trials, according to a statement from the AACR.

The drugs that were featured were ABBV-CLS-484, AMX-818, BAY 2666605, CFT7455, CFT8634, EZM0414, FHD-286, GDC-6036, JNJ-78306358, KSQ-4279, MRTX0902, AMX-818, BAY 2666605, ABBV-CLS-484, JNJ-78306358, and NXP800, CFT8634, GDC-6036, EZM0414, CFT7455, and FHD-286.

For KSQ-4279, the study results showed that the drug when combined with poly (ADP-ribose) polymerase (PARP) inhibitors had clear evidence of synergy in cell lines with partial or no sensitivity to each agent. Investigators used CRISPRomic technology to perform functional genomic resistance screens.

The top-scoring resistance genes for the drug were distinct compared with to those from PARP inhibitors, which suggests that combining PARP and ubiquitin-specific protease 1 inhibitors could provide more durable disease control and reduce resistance.

“These data support the ongoing clinical trial of KSQ-4279 in patients with tumors harboring BRCA1/2 or other homologous recombination deficiency mutations, both as a single agent and in combination with PARP inhibitors,” Andrew Wylie, PhD, from KSQ Therapeutics, said in a statement. “We hope this will make it into the clinic as soon as possible.”

MRTX0902 combined with MRTX849 enhanced the depth and durability of antitumor response in preclinical KRAS-G12C tumor models when compared withto MRTX849 alone.

Additionally, MRTX0902 augments additional targeted therapies across a variety of RAS-addicted tumors, indicating that SOS1 inhibition is effective against a broad spectrum of mutations within the MAPK pathway.

“Furthermore, drug-anchored CRISPR experiments with MRTX0902 and MRTX849 uncovered a previously underappreciated functional role of the SOS1 paralog, SOS2, in KRAS-addicted tumors,” Jacob Haling, PhD, of Mirati Therapeutics, said in the statement.

Another drug in development was AMX-818, a conditionally active masked T-cell engager (TCE) targeting HER2. It is designed to overcome the on-target, off-tumor toxicities that are associated with existing TCEs.

“Extensive in-vitro and in-vivo preclinical testing demonstrated the potential for AMX-818 to drive antitumor activity similar to an unmasked TCE, yet significantly expand the safety margin in NHPs [nonhuman primates],” Bryan Irving, PhD, from Amunix, a Sanofi Company, said in the statement.

The data collected from the studies of AMX-81demonstrated a significant decrease in toxicity from treatment compared withto unmasked TCEs.

Additionally, BAY 2666605, the first PDE3A-SLFN12 complex inducer, was the first velcrin to enter phase 1I clinical trials.

“BAY 2666605 is active in cell line- and patient-derived melanoma xenografts, specifically where elevated levels of the two 2biomarkers, PDE3A and SLFN12, are expressed,” Heidi Greulich, PhD, from the Broad Institute, said in the statement.

Investigators said they also successfully tested the compound in other biomarker-positive tumor types.

It also has drug properties, excellent brain penetration, reduced inhibition of PDE3A inhibitors, and stimulation of SLFN12 RNase activity, and reduced inhibition of PDE3A inhibitors.

The drug has also recently entered into a first-in-human study for individuals with advanced solid tumors that co-express PDE3A and SLFN12, which includes melanoma, ovarian cancer, and sarcoma.

In the second presentation, the first drug featured was ABBV-CLS-484, a selective, active site PTPN2/N1 small-molecule inhibitor. PTPN2/N1 are designed to increase improvethe activation and function of cytotoxic T-cells and increase pro-inflammatory properties.

ABBV-CLS-484 promotes antitumor immunity as both a monotherapy and in combination with anti-PD-1, which leads to tumor regression.

“Our results show that PTPN2/N1 inhibitors have complementary effects on the immune system and tumor microenvironment that act to promote effective tumor killing,” Christina Baumgartner, PhD of AbbVie Inc, said in the statement. “Based on these robust preclinical data, a phase 1I clinical trial of ABBV-CLS-484 alone and in combination with an anti-PD-1 agent have been initiated to establish the safety, tolerability, and efficacy in diverse solid tumor indications.”

Another drug featured wasis JNJ-78306358, a first-in-class bispecific antibody that is used to treat advanced-stage solid tumors.

“JNJ-78306358 induces HLA-G-expressing tumor cell killing via T-cell redirection,” Nataša Obermajer, PhD, from Janssen Research and Development, said in the statement. “JNJ-78306358 demonstrated potent T-cell-mediated in vitro cytotoxicity against HLA-G-expressing tumor cell lines and absence of killing against cancer cells lacking HLA-G membrane expression, highlighting the specificity against antigen-expressing tumor cells.”

The safety, tolerability, and preliminary antitumor activity are being evaluated in a phase 1 trial for advanced-stage solid tumors with high prevalence of HLA-G protein expression.

Another drug examined was NXP800, which exhibited therapeutic activity in xenografts of human clear-cell ovarian cancer, as well as endometroid ovarian cancer.

The efficacy and tolerability data indicated a clear therapeutic window. A phase 1I trial is now open and will assess safety in individuals with advanced solid tumors and then evaluate preliminary antitumor activity in individuals with ARID1A biomarker-selected ovarian clear cell carcinoma and endometrioid carcinoma.

“In addition, we identified deficiency in ARID1A, a component of the SWI/SNF chromatin remodeling complex, as indicative of greater therapeutic responsiveness,” Paul Workman, PhD, from Institute of Cancer Research, said in a statement. “This was confirmed through broader evaluation in human cancer cell line panels, which also indicates therapeutic potential for NXP800 in additional cancer types.”

The final drug for the second presentation was CFT8634, an orally bioavailable heterobifunctional degrader that induces ternary complex formation with BRD9 and an E3 ligase. This leads to ubiquitination of BRD9 and its subsequent degradation by the proteasome.

“CFT8634 is effective at impairing cell growth in a concentration-dependent manner, specifically in SMARCB1-perturbed contexts,” Katrina Jackson, PhD, from C4 Therapeutics, said in the statement. “In vivo, oral dosing of CFT8634 in xenograft models of SMARCB1-perturbed cancers leads to robust and dose-dependent degradation of BRD9, which translates to significant and dose-dependent inhibition of tumor growth in preclinical xenograft models.”

Based on the preclinical profile, a phase 1/2 trial in individuals with synovial sarcoma and SMARCB1-null solid tumors is planned for the first half of 2022.

In the final part of the set of sessions, presenters featured GDC-6036, which is a clinical-stage treatment for KRAS G12C-positive cancers.

“GDC-6036 demonstrates greater potency and selectivity compared with other KRAS G12C inhibitors in vitro, and complete tumor growth inhibition in multiple KRAS G12C-positive cell lines and in xenograft mouse models,” Hans Purkey, PhD, Genentech, said in the statement. “GDC-6036 exhibits significant antitumor efficacy across KRAS G12C-positive models and demonstrates robust preclinical combination activity with other targeted oncology agents.”

The drug is currently in phase 1 clinical development as both a monotherapy and in combination with other agents, including an SHP2 inhibitor.

EZM0414, a first-in-class, potent, selective, orally bioavailable small molecule inhibitor of the enzymatic activity of SETD2 to target B-cell malignancies, was also discussed during the presentation.

A phase 1 trial is currently enrolling individuals and will evaluate the efficacy, safety, and tolerability, efficacy. A phase 2 dose of the drug will be administered as a monotherapy in individuals with relapsed or refractory multiple myeloma and relapsed or refractory diffuse large B-cell lymphoma.

“Ongoing preclinical studies are aimed at defining the mechanism of action of SETD2 inhibition in multiple myeloma and diffuse large B-cell lymphoma, furthering our understanding of the combination potential, and exploring the therapeutic potential in other indications with dysregulated H3K36 methylation,” Jeffery Kutok, MD, PhD, from Epizyme, Inc, said in the statement.

Another drug examined was CFT7455, a novel IKZF1/3 degraded. It is optimized for high-binding affinity to the E3 ubiquitin ligase component cereblon, rapid and deep IKZF1/3 degradation, and potent dose-dependent efficacy in vivo.

“In vivo, CFT7455 catalyzed deep and durable degradation of IKZF3, translating into potent antitumor activity in multiple myeloma xenograft models,” James A. Henderson, PhD, from C4 Therapeutics, said in the statement.

“CFT7455 also retained its activity in models resistant or insensitive to clinically approved IMiDs as a single agent or in combination with the standard-of-care agent dexamethasone. These features make CFT7455 an exciting drug candidate, and it is currently being studied in a phase I clinical trial,.” Henderson said.

The final drug presented was FHD-286, a BAF inhibitor for the treatment of transcription factor-driven cancers. The drug acts through a unique allosteric mechanism. The inhibition of the BAD complex resulted in lineage-specific changes in chromatin accessibility in cancer cell lines.

“FHD-286 is orally bioavailable and demonstrates robust efficacy in multiple cell line- and primary human tumor-derived xenograft models at well-tolerated doses,” Murphy Hentemann, PhD, from Foghorn Therapeutics, said in the statement. “In preclinical efficacy and toxicology studies, this first-in-class molecule demonstrates an acceptable therapeutic index, which should allow for flexibility in clinical designs.”

The drug is currently in 2 phase 1 trials for relapsed refractory acute myeloid leukemia and myelodysplastic syndromes in 1 trial and metastatic uveal melanoma in the other trial.

Reference

Investigators report first disclosures of 12 novel agents during three special sessions. American Association for Cancer Research Meeting News. News release. April 14, 2022. Accessed April 13, 2022. https://www.aacrmeetingnews.org/news/investigators-report-first-disclosures-of-12-novel-agents-during-three-special-sessions/