Summary

• This pre-meeting ESMO24 report is based on a review of the 2,960 abstract titles of which 275 new not yet approved drugs have been identified with a clinical status as follows: first-in-human (31%); other early phase (36%); and late phase (33%). NOTE: additional new drugs will be presented at the conference; however, they are not mentioned specifically by name in the abstract title.

• The focus of this report is to describe the different cancer drug modalities which for which the 275 new drugs have been classified as follows: small molecule (37%), antibody (40%) and “mixed-bag” (23%) which includes cancer vaccines, cell therapy (e.g. CAR-T, TCR, TIL), non-antibody drug conjugates, oncolytic viruses, and radiotherapeutics.

• This report includes a summary of key insights from the recent ASCO24 annual meeting and ASCO24BT meeting in Yokohama, Japan. Of these 275 new drugs to be presented at ESMO24, 118 (43%) of which were presented at these ASCO meetings.

• There are several new cancer drugs that have been approved in China, but not yet in the United States or Europe (as of 12-Sep-2024). For example, cardunilimab, donafenib, flumatinib, penpulimab, pyrotinib, serplulimab, sintilimab, and vebreltinib.  These drugs are excluded from this report, but may be the subject of another report in the future.

• This report is organized based on drug type modality. In some cases, there may be some overlap between groups which is noted accordingly. Information for this report is based on currently available publicly available information which may in some cases include self-reported information from the drug developer. Clinical analytics may be limited in the case where information is missing.

• Please contact me for additional information: rick.beasley@obis.com.

Report Contents

This report is based on the following categories based on popular cancer drug modalities presented clockwise from the pie chart.  There are some exceptions which are noted where applicable.

Antibody: Antibody-Drug Conjugates (ADCs) | BsAb – Bispecific Antibodies | mAb – Monoclonal Antibodies | ICI – Immune Check Point Inhibitors

“Mixed-Bag”: Cancer Vaccines | Other Mixed Bag | Other Drug Conjugates | Oncolytic Viruses | Cell Therapy | Radiotherapeutics

Small Molecules: Non Kinase Inhibitors | Tyrosine Kinase Inhibitors (TKI) | Other Kinase Inhibitors | Protein Degraders/PPI/SERDs | CDK Inhibitors | KRAS Inhibitors | Other SMOL

Antibody-Drug Conjugates (ADCs)

Summary

The basic concept of an ADC dates back to scientist Paul Ehrich’s 1900’s concept of a “magic bullet” to deliver targeted therapeutics (Singh, #ASCO24).

ADCs are emerging as one of the most important cancer drug modalities of the decade with 39 new, not yet approved ADCs to be presented at ESMO24.  There are currently 13 US FDA ADCs approved covering 11 different targets.  The new ESMO24 ADCs cover 17 targets for which there is currently no approved ADC (source: US FDA, ESMO24 abstract titles, OBiS database).

An ADC consists of three main components as the name implies: (1) Antibody; (2) Drug, (3) Conjugate referred to as a linker. There are opportunities in each of these components to optimize both their effectiveness and toxicity profile.

ADC drug payloads are typically small molecule cytotoxic agents some as old as 50 years, for example, Topo I inhibitors based on camptothecin (LoRusso, #ASCO24).

Payloads for the ESMO24 “New” ADCs consist of Topo I inhibitors (56%), Tubulin disrupters (36%), and Undisclosed payloads (8%).  The three undisclosed payloads are associated with the following ADC’s: DS-9606a, SHR-A1904 and XNW27011 (source: OBiS Database).

ADC Linker technology is “pivotal” to the effectiveness of the ADC as a means to limit toxicity and drug resistance (LoRusso, #ASCO24).

About half of approved ADCs are for hematological cancers.  Dr. LoRosso explained that hematological malignancies express “linage specific antigens” whereas solid tumors express tumor associated antigens (i.e. not tumor specific) making their development far more “complicated” (LoRusso, #ASCO2024).  Further, solid tumors are more difficult to access and more heterogeneous as compared to hematological cancers (LoRusso, #ASCO2024).

The majority of approved ADCs are for hematological cancers.  Dr. LoRosso explained that hematological malignancies express “linage specific antigens” whereas solid tumors express tumor associated antigens (i.e. not tumor specific) which poses toxicity challenges and making their development far more “complicated” (LoRusso, #ASCO2024).  Further, solid tumors are more difficult to access and more heterogeneous as compared to hematological cancers (LoRusso, #ASCO2024).

Due to the antibody-targeted nature of the ADC, distribution is often perceived to be limited to the tumor environment; however, based on experimental work cited by Dr Russo, (Bensch et al., 2018), over four days, less than 1% of the ADC antibodies are delivered to the tumor based on ⁸⁹Zr-labeled tracers (Bensch et al., 2018 as cited by LoRusso, #ASCO2024).

Challenges & Opportunities

Resistance

Toxicity

Targeted-Targeted ADCs (e.g. Novartis DYP688)

Neo Adjuvant

References:

Singh, H. (2024). Antibodies Plus: Bispecifics, Antibody Drug Conjugates, and Engagers in Solid Tumors [Conference presentation]. 2024 ASCO Annual Meeting, American Society of Clinical Oncology, Dana-Farber Cancer Institute, Boston. https://meetings.asco.org/2024-asco-annual-meeting/15692.

LoRusso, P. M. (2024). Mechanisms of resistance to ADCs [Conference presentation]. 2024 ASCO Annual Meeting, American Society of Clinical Oncology, Chicago, IL, United States.  https://meetings.asco.org/2024-asco-annual-meeting/15727

Bensch, F., Smeenk, M. M., van Es, S. C., de Jong, J. R., Schröder, C. P., Oosting, S. F., Lub-de Hooge, M. N., Menke-van der Houven van Oordt, C., Brouwers, A. H., Boellaard, R., & de Vries, E. G. E. (2018). Comparative biodistribution analysis across four different 89Zr-monoclonal antibody tracers—The first step towards an imaging warehouse. Theranostics, 8(16), 4295-4304. https://doi.org/10.7150/thno.26370

BsAb – Bispecific Antibodies

Summary

Included in this section are tri-specifics CB307 (4-1BB x HSA x PSMA) and SAR443216 (CD28 x CD3 x HER2), tetra-specific MDX2001 (engages T-cells and tumor antigens).

Bispecific Immune Checkpoint Inhibitors (ICIs) account for 23% of the 32 new BsAb to be presented at ESMO24.  CD3 (i.e. Bispecific T-Cell Engagers, BiTes) make up 12% and T-cell co-stimulatory targets CD28 and 41BB.  The remaining 54% consists of twenty different targets such as HER2, DLL3, EGFR (source: ESMO24 abstract titles and OBiS database).

Bispecific T-Cell Engagers, BiTes

BiTes bind CD3 on T-cell and the neoantigen on the tumor cell bringing these two cells closer together and facilitating immunity.  The neoantigen specific T cell “is the fundamental mediator of anti tumor immunity (Singh, H. #ASCO24)”.  By engineering a T-cell receptor (TCR) that will bind to a specific tumor neoantigen and connecting it with a T-cell CD3, bystander T cells can be additionally engaged to increase the immune response (Singh, H. #ASCO24)

References

Singh, H. (2024). Antibodies Plus: Bispecifics, Antibody Drug Conjugates, and Engagers in Solid Tumors [Conference presentation]. 2024 ASCO Annual Meeting, American Society of Clinical Oncology, Dana-Farber Cancer Institute, Boston. https://meetings.asco.org/2024-asco-annual-meeting/15692.

mAb – Other Monoclonal Antibodies

Summary

Important Note: This section excludes ADCs, BsAb, and ICIs.  This section is essentially the all other antibodies.

ICI – Immune Check Point Inhibitors

Summary

Pending update

Cancer Vaccines

Summary

Pending update

Other “Mixed Bag”

Summary

Pending update

Other Drug Conjugates

Summary

Bicycle toxin conjugates (BTCs) are an emerging class of therapeutics.  BTCs are similar to ADCs, except they use a peptide conjugate instead of an antibody to bind to their target.

Oncolytic Virus

Summary

Update pending

Cell Therapy

Summary

Update pending

Radiotherapeutics

Summary

Update pending

Non Kinase Inhibitors

Summary

Update pending

Tyrosine Kinase Inhibitors (TKI)

Summary

Update pending

Other Kinase Inhibitors

Summary

Update pending

Protein Degraders/PPI/SERDs

Summary

Update pending

CDKi – Cyclin-Dependent Kinase Inhibitors

Summary

Update pending

KRAS Inhibitors (Kirsten Rat Sarcoma viral oncogene homolog)

Summary

KRAS has long been considered one of the most important oncogenes to target as genetic mutations in the RAS family, which includes KRAS, HRAS, and NRAS, account for 27% of all tumors (Merz et al., 2021).

In Non-Small Cell Lung Cancer (NSCLC), KRAS mutations account for 30% of all cases of which KRAS G12C mutations account for the largest subtype (44%), followed by G12D (16%), G12V (15%), G12A (7%), G13D (5%) (Choudhury, N. J., et al., 2023, Arbour, K. C., et al. 2018 as cited by Arbour, ASCO24).

Challenges and Opportunities

Combinations: KRAS pathway is complex and many different components in the pathway can affect cancer progression, thus there are many different combination strategies being explored that “are rooted in clear biologic rationale”, for example: OLOMORASIB (KRAS G12C inhibitor) + PEMBROLIZUMAB (PD-1 inhibitor); FULZERASIB (KRAS G12C Inhibitor) + CETUXIMAB (EGFR inhibitor);  SOTORASIB ((KRAS G12C Inhibitor) + CHEMO (Arbour, ASCO24).

Co-mutations, such as p53, SDK11 and KEAP1, are common in lung adenocarcinoma and play a significant role in drug resistance pathways and disease severity (Arbour, ASCO24).

References

Merz, V., Gaule, M., Zecchetto, C., Cavaliere, A., Casalino, S., Pesoni, C., Contarelli, S., Sabbadini, F., Bertolini, M., Mangiameli, D., Milella, M., Fedele, V., & Melisi, D. (2021). Targeting KRAS: The elephant in the room of epithelial cancers. Frontiers in Oncology, 11, Article 638360. https://doi.org/10.3389/fonc.2021.638360.

Arbour, K. C. (2024). The science of targeting KRAS. Memorial Sloan Kettering Cancer Center. Presented at the 2024 ASCO Annual Meeting, American Society of Clinical Oncology.  https://meetings.asco.org/2024-asco-annual-meeting/15682?presentation=236911.

Choudhury, N. J., Lavery, J. A., Brown, S., de Bruijn, I., Jee, J., Tran, T. N., Rizvi, H., Arbour, K. C., Whiting, K., Shen, R., Hellmann, M., Bedard, P. L., Yu, C., Leighl, N., LeNoue-Newton, M., Micheel, C., Warner, J. L., Ginsberg, M. S., Plodkowski, A., … Riely, G. J.; AACR GENIE BPC Core Team. (2023). The GENIE BPC NSCLC cohort: A real-world repository integrating standardized clinical and genomic data for 1,846 patients with non-small cell lung cancer. Clinical Cancer Research, 29(17), 3418-3428. https://doi.org/10.1158/1078-0432.CCR-23-0580

Arbour, K. C., Jordan, E., Kim, H. R., Dienstag, J., Yu, H. A., Sanchez-Vega, F., Lito, P., Berger, M., Solit, D. B., Hellmann, M., Kris, M. G., Rudin, C. M., Ni, A., Arcila, M., Ladanyi, M., & Riely, G. J. (2018). Effects of co-occurring genomic alterations on outcomes in patients with KRAS-mutant non-small cell lung cancer. Clinical Cancer Research, 24(2), 334-340. https://doi.org/10.1158/1078-0432.CCR-17-1841

Other Small Molecules

Summary

Update pending