10 Most Promising Cancer Drugs Not Yet Approved: Solid Tumors – 2024 edition by OncoDaily

In the fast-growing field of oncology, we are witnessing significant advances in several treatment modalities that may soon change how cancer is treated. While not yet FDA-approved, these ten future cancer drugs have captured our attention due to their impressive preliminary data and the potential to offer new solutions for various malignancies.

Our editorial team has highlighted these key candidates, each of whom holds promise to transform patient care with their innovative treatment approaches. These promising cancer drugs signal a potential shift in the approach to treating this complex group of diseases.

Datopotamab deruxtecan (Dato-DXd)

Company: AstraZeneca, Plc and Daiichi Sankyo Co., Ltd.

Being tested for: NSCLC, Breast cancer, and Pan-tumor trials

Datopotamab deruxtecan (Dato-DXd) is an investigational antibody-drug conjugate (ADC) targeting TROP2, a cell surface protein overexpressed in various types of cancer, including non-small cell lung cancer (NSCLC) and triple-negative breast cancer (TNBC).

Dato-DXd combines a humanized anti-TROP2 IgG1 monoclonal antibody with topoisomerase I inhibitor payload (an exatecan derivative, DXd) via tetrapeptide-based cleavable linkers. This design allows targeted delivery of the cytotoxic payload directly to tumor cells while minimizing exposure to healthy tissues.

Dato-DXd is evaluated in more than 14 trials, testing its efficacy and safety across various types of cancer. Notable trials include TROPION-Lung01 (NCT03401385), a phase III trial assessing datopotamab deruxtecan against docetaxel in patients with previously treated advanced/metastatic NSCLC.

The trial showed a median progression-free survival (PFS) of 4.4 months for datopotamab deruxtecan compared with 3.7 months for docetaxel, with a hazard ratio (HR) of 0.75 (95% CI: 0.62–0.91; p=0.004).

The interim overall survival (OS) was 12.4 months with datopotamab deruxtecan compared with 11.0 months for docetaxel (HR 0.90; 95% CI: 0.72–1.13). The objective response rate (ORR) was 26.4% with datopotamab deruxtecan, compared with 12.8% with docetaxel.

In the phase I TROPION-PanTumor01 (NCT03401385) study), datopotamab deruxtecan was evaluated for HR+/HER2- and triple-negative breast cancer (TNBC). The study reported a confirmed ORR of 26.8% in HR+/HER2- breast cancer and 31.8% in TNBC.

The median duration of response (DoR) was 10.5 months, with a median progression-free survival (PFS) of 6.9 months and a median overall survival (OS) of 11.4 months across a mixed patient population.

The phase 1b/2 BEGONIA trial (NCT03742102) explored datopotamab deruxtecan in combination with durvalumab in metastatic TNBC. The trial achieved a confirmed ORR of 79%, including six complete responses (CRs) and 43 partial responses (PRs). The median PFS was 13.8 months, and the median DoR was 15.5 months.

The phase III TROPION-Breast01 trial (NCT05104866) compared datopotamab deruxtecan with chemotherapy in patients with HR-positive, HER2-low or negative breast cancer.

Datopotamab deruxtecan reduced the risk of disease progression or death by 37%, demonstrating a median improvement in PFS at 2 months. Confirmed ORR was 36.4% in patients treated with datopotamab deruxtecan.

The FDA has accepted a Biologics License Application (BLA) for approval of datopotamab deruxtecan (Dato-DXd) for use in adult patients with unresectable or metastatic hormone receptor-positive, HER2-negative breast cancer who have previously received systemic therapy for their advanced disease.

Botensilimab

Company: Agenus, Inc.

Being tested for: Colorectal Cancer, Sarcoma, Ovarian Cancer, GEJ, Kidney, Melanoma, Pan-tumor Basket trial for different cancers

Botensilimab, also known as AGEN1181, is a next-generation anti-CTLA-4 monoclonal antibody designed to optimize T-cell priming, activation, and memory formation while promoting regulatory T-cell depletion within tumors.

This next-generation antibody uniquely features an Fc-enhanced profile that does not bind to the Fc receptor on effector cells, which is believed to reduce toxicity associated with traditional CTLA-4 targeting therapies. Botensilimab targets CTLA-4, a checkpoint inhibitor that downregulates the immune response, thereby enhancing the body’s ability to fight cancer.

The phase 1/2 trial in heavily pretreated MSS Colorectal cancer patients (NCT03860272) has shown promising results, achieving an objective response rate (ORR) of 22% and a disease control rate (DCR) of 73%.

Another significant trial, NCT05672316, is investigating the combination of botensilimab with balstilimab and regorafenib in treating patients with MSS metastatic colorectal cancer, focusing on safety, tolerability, and preliminary anti-tumor activity.

The phase I NEST-1 trial (NCT05571293) demonstrated the activity of botensilimab and balstilimab in patients with hard-to-treat “cold” MSS tumors.

In this neoadjuvant trial botensilimab and balstilimab resulted in significant tumor reductions and prolonged ctDNA/minimal residual disease (MRD) negativity in patients with resectable mismatch repair–proficient (pMMR) and deficient (dMMR) colorectal cancer.

In the study, 67% of microsatellite stable (MSS) CRC patients achieved pathological responses, with 100% of microsatellite instability-high (MSI-H) CRC patients experiencing major pathological responses. The regimen was well-tolerated, with no patients experiencing severe adverse effects or delayed surgery.

In the phase 1b trial (NCT03860272) botensilimab in combination with balstilimab demonstrated significant efficacy in treating refractory metastatic sarcomas. The study reported an objective response rate (ORR) of 27% among 22 evaluable patients, with a disease control rate (DCR) of 68%. The median duration of response was not reached, indicating a sustained effect.

Progression-free survival (PFS) at six months was 50%, and the 12-month overall survival (OS) rate was 82%. The safety profile remained manageable, with no grade 4 or 5 treatment-related adverse events reported.

Currently, botensilimab is being evaluated in several clinical trials for its efficacy and safety in treating various types of cancer, including microsatellite stable (MSS) colorectal cancer (CRC), sarcomas, gastric, and gastro-esophageal junction cancers.

In April 2023, the FDA granted Fast Track Designation to the combination of botensilimab (AGEN1181) and balstilimab (AGEN2034) for the treatment of patients with metastatic non–microsatellite instability-high (MSI-H)/mismatch repair–deficient (dMMR) colorectal cancer (mCRC) with no active liver involvement.

Sunvozertinib

Company: Dizal (Jiangsu) Pharmaceutical Co., Ltd and AstraZeneca, Plc

Being tested for: NSCLC

Sunvozertinib, also known as DZD9008, is an innovative, orally administered, irreversible EGFR inhibitor that specifically targets EGFR exon 20 insertion mutations, a less common but clinically significant form of mutation in non-small cell lung cancer (NSCLC).

Sunvozertinib is designed to selectively inhibit these mutations while maintaining selectivity against wild-type EGFR, which helps to minimize toxicity typically associated with EGFR targeting.

Sunvozertinib has been included in several clinical trials. Notably, the WO-KONH6 study (NCT05712902), a phase II trial, demonstrated significant antitumor activity in Chinese patients with NSCLC harboring EGFR exon 20 insertion mutations.

The study reported an objective response rate (ORR) of 60.8% with a disease control rate (DCR) of 87.6% when administered at 300 mg once daily. Another pivotal trial, WU-KONG28 (NCT05668988), is a multinational, phase III, randomized study comparing sunvozertinib with chemotherapy as a first-line treatment for NSCLC with EGFR exon20ins mutations.

The safety profile of sunvozertinib was consistent with that of other EGFR tyrosine kinase inhibitors, with the most common treatment-emergent adverse events (TEAEs) being diarrhea, rash, and anemia. These events are generally manageable and predominantly of low severity.

Sunvozertinib’s development represents a significant advance in targeted therapy for patients with NSCLC with specific genetic alterations, offering a new therapeutic option for a subgroup of patients who previously had limited treatment choices. Its approval and clinical use are anticipated to provide improved outcomes for patients with this challenging form of lung cancer.

Based on the results from the phase 1/2 WU-KONG1 trial, in April 2024, the FDA has granted Breakthrough Therapy Designation to sunvozertinib.

Zolbetuximab

Company: Astellas Pharma, Inc.

Being tested for: Gastric adenocarcinoma, GEJ

Zolbetuximab, also known by its development code IMAB362 and sold under the brand name Vyloy, is a chimeric monoclonal immunoglobulin G1 antibody targeting Claudin-18.2 (CLDN18.2), a protein expressed on the surface of gastric epithelial cells.

This antibody is designed to selectively bind to CLDN18.2, initiating tumor cell death through mechanisms such as antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC).

Zolbetuximab has been under investigation for the treatment of gastrointestinal adenocarcinomas and pancreatic tumors. It has been evaluated in several clinical trials, including the SPOTLIGHT (NCT03504397) and GLOW (NCT03653507) phase III trials, which assessed its efficacy in combination with chemotherapy regimens like mFOLFOX6 and CAPOX, respectively.

In the GLOW study, the addition of zolbetuximab to CAPOX resulted in a median overall survival (OS) of 14.39 months compared with 12.16 months for the placebo group, with a hazard ratio (HR) of 0.771 (95% CI, 0.615–0.965; P=0.0118). These trials demonstrated the potential of zolbetuximab to improve survival outcomes in patients with CLDN18.2-positive gastric or gastroesophageal junction (GEJ) adenocarcinoma.

Despite its promising clinical profile, as of early 2024, zolbetuximab has not yet received regulatory approval in the U.S., with the FDA issuing a complete response letter due to unresolved issues at a third-party manufacturing facility. However, it has been approved in Japan for the treatment of gastric cancer.

Glecirasib

Company: Jacobio Pharmaceuticals

Being tested for: Pancreatic cancer, NSCLC, and Other cancers with G12C mutation

Glecirasib is a novel KRAS G12C inhibitor targeting the KRAS G12C mutation found in various solid tumors, including non-small cell lung cancer (NSCLC) and colorectal cancer (CRC). This mutation is a specific genetic alteration that is critical to tumor growth and survival. Glecirasib acts by covalently binding to the mutated KRAS G12C protein, locking it in an inactive state, which inhibits tumor cell proliferation and induces cell death.

The drug has been evaluated in several clinical trials. Notably, the phase II registrational study of glecirasib in KRAS G12C mutation-positive NSCLC patients previously treated with platinum-based therapy and an immune checkpoint inhibitor (ICI) met its primary endpoint.

This study, identified as NCT05009329, reported a confirmed objective response rate (cORR) of 47.9% (95% CI, 38.5%-57.3%), with a median progression-free survival (mPFS) of 8.2 months (95% CI, 5.5-13.1) and a median overall survival (mOS) of 13.6 months (95% CI, 10.9-not evaluable [NE]). The disease control rate (DCR) was 86.3% (95% CI, 78.7%-92%), and the median duration of response (DOR) was not reached (95% CI, 7.2-NE).

Glecirasib demonstrated a manageable safety profile with low incidences of gastrointestinal side effects compared with other KRAS G12C inhibitors. Treatment-related adverse events were common but manageable, with serious events reported in 19.3% of patients and no grade 5 events observed.

Another study on glecirasib in 52 patients with KRAS G12C-mutated pancreatic and other solid tumors demonstrated a promising objective response rate (cORR) of 48% and a disease control rate (DCR) of 90%.

Particularly, in pancreatic cancer patients receiving second-line therapy or beyond, glecirasib achieved a cORR of 41.9% and a DCR of 93.5%, with a median progression-free survival (mPFS) of 5.6 months and overall survival (mOS) of 10.7 months, showcasing its potential as a superior treatment for these mutations.

These results highlight glecirasib’s potential as a promising treatment option for patients with KRAS G12C-mutated cancers, offering a new therapeutic avenue with a favorable safety and efficacy profile.

In April 2024, Glecirasib received FDA orphan drug designation for pancreatic cancer and was previously granted Breakthrough Therapy Designation by China’s CDE for second-line or higher treatment in patients with this mutation.

Rinatabart sesutecan

Company: ProfoundBio (Suzhou) Co., Ltd.

Being tested for: Ovarian cancer, Endometrial cancer, Breast cancer, NSCLC, Mesothelioma

Rinatabart sesutecan (Rina-S; PRO1184) is an investigational antibody-drug conjugate (ADC), targeting folate receptor alpha (FRα), a protein frequently overexpressed in various cancers, including ovarian and endometrial cancers.

This novel ADC comprises a monoclonal antibody directed against FRα, linked to the cytotoxic agent exatecan via a hydrophilic, cleavable linker. This design facilitates the delivery of the potent topoisomerase 1 inhibitor directly to cancer cells, minimizing systemic toxicity while maximizing antitumor efficacy.

Rinatabart sesutecan is currently being evaluated in a phase 1/2 clinical trial (NCT05579366), known as PRO1184-001. This study is designed to assess the safety, tolerability, pharmacokinetics (PK), and antitumor activity of the drug in patients with selected locally advanced and/or metastatic solid tumors, including epithelial ovarian cancer, endometrial cancer, breast cancer, non-small cell lung cancer, and mesothelioma.

The trial consists of two parts: Part A (Dose Escalation) and Part B (Dose Expansion). Initial results presented at the Society for Immunotherapy of Cancer (SITC) 2023, demonstrated encouraging the antitumor activity of rinatabart sesutecan with an objective response rate (ORR) of 67% (8 out of 12 patients) in evaluable patients with ovarian and endometrial cancer displaying FRα expression above 1% in their tumors.

Among these responses, there were 3 partial responses (PRs) in patients with less than 25% FRα expression based on 1+ immunohistochemistry staining intensity. Over time, the responses typically intensified at doses ranging from 60 to 140 mg/m2, including a complete response (CR) in one patient with ovarian cancer who was treated with two doses of rinatabart sesutecan and had prior treatment with mirvetuximab soravtansine (Elahere).

The FDA has granted Fast Track Designation to rinatabart sesutecan for the treatment of patients with FRα-expressing high-grade serous or endometrioid platinum-resistant ovarian cancer, highlighting its potential to address unmet medical needs in this challenging therapeutic area.

Tiragolumab

Company: Genentech, Inc.

Being tested for: Lung cancer, Esophageal cancer, Cervical cancer, and Pan-tumor trials

Tiragolumab, also known as MTIG7192A or RG6058, is a monoclonal antibody that targets the T cell immunoreceptor with Ig and ITIM domains (TIGIT), an immune checkpoint receptor that plays a critical role in suppressing the immune response.

By inhibiting TIGIT, tiragolumab aims to enhance the immune system’s ability to fight cancer. This mechanism involves blocking the interaction between TIGIT and its ligands, which can lead to an increased activation of T cells and natural killer (NK) cells, enhancing anti-tumor activity.

Tiragolumab is investigated in various clinical trials, including the SKYSCRAPER, CITYSCAPE, and MORPHEUS trials.

The CITYSCAPE trial showed more promising results in NSCLC, with tiragolumab in combination with atezolizumab demonstrating an improved overall response rate (ORR; 37% vs. 21% with atezolizumab alone) and a 42% reduction in the risk of disease worsening or death (PFS) compared with atezolizumab alone.

SKYSCRAPER-08 trial, a phase III study, evaluated the efficacy of tiragolumab in combination with atezolizumab and chemotherapy in patients with esophageal squamous cell carcinoma (ESCC).  Of 461 Asian patients with ESCC, 88% had a PD-L1 TAP of ≥1%, ORR was 59.7% compared with 45.5% in controls.

Additionally, median progression-free survival (mPFS) improved to 6.2 months from 5.4 months, and median overall survival (mOS) increased to 15.7 months versus 11.1 months in the placebo group.

Additionally, the MORPHEUS-EC trial (NCT032813690), a phase Ib/II study, also focused on first-line treatment with tiragolumab in combination with atezolizumab and chemotherapy in patients with esophageal cancer, demonstrated an increase in the objective response rate (ORR) to 67.7%, versus 47.8% with chemotherapy alone, and increased median progression-free survival (PFS) to 6.9 months from 4.1 months.

The MORPHEUS-liver study (NCT04524871) showed that the addition of tiragolumab to standard atezo + bev therapy for untreated uHCC significantly improved the objective response rate (ORR) to 42.5% from 11.1% and increased median progression-free survival (PFS) to 11.1 months compared with 4.2 months in the control group (HR 0.42).

The FDA has granted Breakthrough Therapy Designation to the anti-TIGIT therapy tiragolumab when used alongside atezolizumab in treating patients with metastatic non-small cell lung cancer with PD-L1 high tumors devoid of EGFR or ALK abnormalities.

Bemarituzumab

Company: Amgen, Inc.

Being tested for: Gastric, GEJ, Bladder, and Other Solid Tumors with FGFR2b Overexpression

Bemarituzumab, also known as FPA144, is a humanized monoclonal antibody that selectively targets the fibroblast growth factor receptor 2b (FGFR2b). It functions by blocking the binding of fibroblast growth factors to FGFR2b, inhibiting several downstream signaling pathways that promote tumor growth and survival. This targeted approach is particularly relevant for gastric and gastroesophageal junction cancers that overexpress FGFR2b.

The drug has been evaluated in the FIGHT trial (NCT03694522), a randomized phase II study designed to assess the efficacy and safety of bemarituzumab in combination with modified FOLFOX6 (mFOLFOX6) chemotherapy.

The study achieved a median progression-free survival (PFS) of 9.5 months in the bemarituzumab group compared with 7.4 months in the placebo group, with a hazard ratio (HR) of 0.72, (p-value = 0.073). Overall survival (OS) also favored the treatment arm, showing a median OS of 19.2 months versus 13.5 months in the placebo group, with an HR of 0.77.

Patients with ≥10% FGFR2b-positive tumor cells showed more pronounced benefits. The trial’s results have led to ongoing confirmatory phase III trials (NCT05052801, NCT05111626) to validate these findings further.

Further research and development continue, with bemarituzumab being studied in additional clinical settings and combinations, such as the phase III FORTITUDE-102 study (NCT05111626), which evaluates bemarituzumab in combination with chemotherapy and nivolumab versus chemotherapy and nivolumab monotherapy in subjects with previously untreated metastatic gastric or gastroesophageal junction cancer.

These studies continue to assess the therapeutic potential and safety profile of bemarituzumab in a broader clinical context.

The FDA has granted a Breakthrough Therapy Designation to bemarituzumab in combination with mFOLFOX6 as a first-line treatment for patients with FGFR2b–overexpressing and HER2-negative metastatic and locally advanced gastric and gastroesophageal (GEJ) adenocarcinoma.

Zenocutuzumab

Company: Merus N.V

Being tested for: NRG1 fusion non-small cell lung cancer (NSCLC), NRG1 fusion pancreatic cancer (PDAC)

Zenocutuzumab, also known as ZW25, is an investigational humanized IgG1 bispecific antibody targeting HER2 and HER3 receptors. This drug is designed to inhibit the neuregulin/HER3 tumor-signaling pathway in solid tumors with NRG1 fusions, which are rare but clinically significant mutations found in various cancers, including non-small cell lung cancer (NSCLC) and pancreatic ductal adenocarcinoma (PDAC).

Zenocutuzumab has been evaluated in the eNRGy trial (NCT02912949), a phase 1/2 study involving patients with NRG1 fusion-positive NSCLC, PDAC, and other solid tumors. In NSCLC patients, the objective response rate (ORR) was 34% with a median duration of response (DOR) of 12.9 months. For pancreatic cancer patients, the ORR was 42%. These results support the efficacy of zenocutuzumab in treating NRG1 fusion-positive cancers.

The safety profile of zenocutuzumab has been generally manageable, with the most common treatment-related adverse events (TRAEs) including diarrhea, asthenia/fatigue, nausea, and infusion-related reactions. No clinical cardiotoxicity was reported, and less than 1% of patients discontinued treatment due to toxicity.

Zenocutuzumab has received a Breakthrough Therapy Designation from the FDA for NRG1 fusion-positive NSCLC and pancreatic cancer. Additionally, the FDA has granted priority review to a Biologics License Application (BLA) for zenocutuzumab for the treatment of NRG1 fusion-positive NSCLC and pancreatic cancer.

mRNA-4157/V940

Company: Moderna, Inc., in collaboration with Merck & Co., Inc.

Being tested for: Melanoma

mRNA-4157/V940 is an investigational mRNA-based personalized cancer vaccine designed to stimulate an immune response by generating specific T-cell responses based on the unique mutational signature of a particular patient’s tumour.

The vaccine is encapsulated in solid lipid nanoparticles and consists of up to 34 mRNA sequences that encode neoantigens, abnormal proteins found on the surface of the patient’s cancer cells. Upon administration, these neoantigen sequences are translated by the patient’s cells, leading to an immune response aimed at targeting and destroying tumour cells.

In the phase II KEYNOTE-942 trial (NCT03897881), the combination of mRNA-4157 and pembrolizumab versus pembrolizumab alone was tested as adjuvant therapy for resected high-risk melanoma.

The results favored the combination therapy, demonstrating improved recurrence-free survival with a hazard ratio of 0.561 (95% CI, 0.309–1.017; p=0.053) and a lower recurrence or death rate of 22% compared with 40% in the monotherapy group.

The 18-month recurrence-free survival rate was markedly better at 79% for those receiving the combination therapy versus 62% for those on monotherapy.

While the majority of adverse events were mild, severe events (Grade ≥3) were slightly more common in the combination group at 25% versus 18% in the monotherapy group, with the incidence of immune-mediated adverse events being equally manageable across both groups (36%).

Following promising results from the KEYNOTE-942 trial, a phase III multicenter INTerpath-001 trial (NCT05933577) is currently underway to further evaluate the efficacy of adjuvant V940 (mRNA-4157) plus pembrolizumab versus placebo plus pembrolizumab in participants with high-risk stage II-IV melanoma.

The FDA has granted a Breakthrough Therapy Designation to the investigational personalized mRNA cancer vaccine mRNA-4157/V940 in combination with pembrolizumab for the adjuvant treatment of patients with high-risk melanoma following complete resection.

Read the 10 Most Promising Cancer Drugs in 2024: What Patients Need to Know here.