Breakthrough Clinical Results
Cantargia announced the publication of clinical trial results in Investigational New Drugs, showing the potential of nadunolimab combined with pembrolizumab in treating heavily pre-treated solid tumor patients who progressed on prior immune checkpoint inhibitors. The trial, involving 15 patients, demonstrated an acceptable safety profile and a median overall survival of 19.7 months. The greatest survival benefit was seen in patients with high levels of immune cells in their tumor microenvironment. These findings suggest a potential new treatment option for patients with limited treatment choices after immunotherapy failure.
Key Highlights
- Publication of clinical data in Investigational New Drugs journal.
- Median overall survival of 19.7 months observed in heavily pre-treated solid tumor patients.
- Greatest survival benefit seen in patients with high baseline levels of infiltrating immune cells.
- Acceptable safety profile reported.
Incidence and Prevalence
Solid tumors, excluding non-melanoma skin cancers, accounted for an estimated 18.1 million new cases globally in 2020. This represents a significant portion of the global cancer burden.
Breaking down the incidence by specific tumor types, the most frequently diagnosed cancers in 2020 were:
- Breast cancer: 2.3 million new cases
- Lung cancer: 2.2 million new cases
- Colorectal cancer: 1.9 million new cases
- Prostate cancer: 1.4 million new cases
- Stomach cancer: 1.1 million new cases
The incidence rates varied considerably across different regions of the world. Australia and New Zealand reported the highest incidence rates for melanoma, while Australia and New Zealand, North America, Northern Europe, and Western Europe had the highest incidence rates for several other cancer types, including breast, lung, colorectal, and prostate cancers. Lower incidence rates were generally observed in Asia and Africa.
In terms of prevalence, the estimated number of people living with cancer (diagnosed within the past 5 years) was 28.8 million in 2008. Almost half of this prevalence burden was concentrated in areas with very high human development, despite these areas comprising only one-sixth of the world's population. Breast cancer was the most prevalent cancer in most countries, while cervical cancer was most prevalent in parts of Sub-Saharan Africa and Southern Asia. Prostate cancer was dominant in North America, Oceania, and Northern and Western Europe. Other prevalent cancers included stomach cancer in East Asia, oral cancer in Indian men, and Kaposi sarcoma in men in several Sub-Saharan African countries.
It's important to note that these are estimates, and the actual incidence and prevalence may vary. Data collection and reporting methods differ across countries and regions, which can affect the accuracy of these figures. Furthermore, the incidence and prevalence of specific cancer types can be influenced by various factors, including genetics, lifestyle, environmental exposures, and access to healthcare.
Emerging Mechanism of Action
Cancer immunotherapy has emerged as a revolutionary approach to treating solid tumors, offering significant improvements in patient survival and quality of life. Several key mechanisms of action (MoAs) are driving this progress:
-
Immune Checkpoint Inhibitors: These agents block immune checkpoints like PD-1, PD-L1, and CTLA-4, which normally suppress T cell activity. By inhibiting these checkpoints, T cells are unleashed to attack tumor cells more effectively. While promising, their success in solid tumors has been limited by factors such as the immunosuppressive tumor microenvironment, inefficient trafficking of immune cells to the tumor site, and heterogeneity of tumor antigens. High intra-tumoral pressure further complicates drug delivery. Research is focused on overcoming these barriers to enhance efficacy in solid tumors.
-
Tyrosine Kinase Inhibitors (TKIs): TKIs target specific tyrosine kinases involved in tumor growth and progression. They inhibit these kinases from phosphorylating their substrates, thereby blocking downstream signaling pathways crucial for tumor development. Over the past two decades, numerous robust and well-tolerated TKIs have been developed, targeting various kinases like EGFR, ALK, ROS1, HER2, NTRK, VEGFR, RET, MET, MEK, FGFR, PDGFR, and KIT. TKIs have dramatically improved survival and quality of life for patients with various solid tumors, significantly shifting treatment paradigms. Ongoing research aims to refine TKI therapies and expand their application in precision cancer medicine.
-
Chimeric Antigen Receptor (CAR) T-cell Therapy: CAR T-cell therapy involves genetically engineering a patient's T cells to express a chimeric antigen receptor that targets a specific tumor antigen. These modified T cells are then infused back into the patient to recognize and destroy tumor cells. While highly successful in hematological malignancies, CAR T-cell therapy faces challenges in solid tumors, including the immunosuppressive tumor microenvironment and difficulty in identifying suitable tumor-specific antigens. Research is ongoing to adapt CAR T-cell therapy for effective use against solid tumors.
-
Anti-angiogenic Therapy: Bevacizumab, a VEGF-A-targeting monoclonal antibody, is a key example of this MoA. It inhibits angiogenesis, the formation of new blood vessels that supply tumors with nutrients and oxygen, thereby hindering tumor growth. Initially approved for metastatic colorectal cancer, bevacizumab is now used for various solid tumors, including metastatic breast cancer, non-small cell lung cancer, glioblastoma, renal cell carcinoma, ovarian cancer, and cervical cancer. Recent research has revealed bevacizumab's immunomodulatory properties, leading to its investigation in combination with cancer immunotherapy. However, the lack of reliable biomarkers for personalized use remains a challenge.
-
TIM-3 Inhibition: TIM-3 is an immune checkpoint molecule expressed on various immune and tumor cells. Studies have shown that TIM-3 protein overexpression is associated with poor overall survival in solid cancers. It is also linked to lymph node metastasis, tumor grade, and PD-1 expression. Research suggests that TIM-3 has potential as both a prognostic marker and a therapeutic target in solid tumors.
In summary, the past three years have seen continued development and refinement of these MoAs, with a focus on improving efficacy in solid tumors. Research efforts are directed towards overcoming the challenges posed by the tumor microenvironment, identifying optimal targets, and developing combination therapies to maximize therapeutic benefit.
Recent Studies
Here's a summary of recent studies on solid tumors, including study names, interventions, and key safety/efficacy outcomes:
1. LY3321367 in Advanced Solid Tumors:
- Study Name: Phase Ia/b study of LY3321367
- Intervention: Novel TIM-3 mAb LY3321367 alone or with anti-PD-L1 antibody LY300054
- Efficacy: Modest antitumor activity. In NSCLC monotherapy, varied outcomes based on prior anti-PD-1 therapy response: refractory patients (N = 23) had 0% ORR, 35% DCR, and 1.9 months PFS; responders (N = 14) had 7% ORR, 50% DCR, and 7.3 months PFS. Combination cohorts (N = 91) had 4% ORR and 42% DCR.
- Safety: Acceptable safety profile. Common treatment-related AEs included pruritus, rash, fatigue, anorexia, and infusion reactions.
2. Dostarlimab in Endometrial Cancer:
- Study Name: GARNET phase I trial
- Intervention: Dostarlimab
- Efficacy: Durable antitumor activity in dMMR/MSI-H EC. ORR: 45.5% (dMMR/MSI-H) and 15.4% (MMRp/MSS). Median DOR not reached for dMMR/MSI-H (median follow-up 27.6 months); 19.4 months for MMRp/MSS.
- Safety: Consistent with previous reports.
3. Savolitinib in Solid Tumors:
- Study Name: Phase I study of savolitinib
- Intervention: Savolitinib
- Efficacy: Promising responses in gastric cancer with c-Met amplification (35.7% ORR, 64.3% DCR) and NSCLC with MET exon 14 skipping mutation (target lesion shrinkage in 2 of 4 patients).
- Safety: Acceptable safety profile. Most frequent treatment-related AEs: nausea (29.4%), vomiting (27.1%), and peripheral edema (21.2%).
4. TILT-123 in Advanced Solid Cancers:
- Study Name: TUNIMO (NCT04695327)
- Intervention: Oncolytic adenovirus TILT-123 (igrelimogene litadenorepvec) armed with TNFα and IL2
- Efficacy: Antitumor effects in injected and non-injected lesions. DCR: 60% by PET, 20% by RECIST 1.1 and iRECIST.
- Safety: Safe; no dose-limiting toxicities. Most frequent treatment-related AEs: fever (16.7%), chills (13%), and fatigue (9.3%).
5. Tiragolumab Plus Atezolizumab in Solid Tumors:
- Study Name: YP42514
- Intervention: Tiragolumab plus atezolizumab
- Efficacy: Tolerable with preliminary anti-tumor activity. Two patients (10%) achieved partial response.
- Safety: Consistent with the global GO30103 study.
6. Toripalimab in Metastatic Urothelial Carcinoma:
- Study Name: Study of toripalimab in mUC
- Intervention: Toripalimab
- Efficacy: Encouraging clinical activity. ORR: 26%, DCR: 45%. Median DOR: 19.7 months, PFS: 2.3 months, OS: 14.4 months. PD-L1 and TMB-high patients had better ORR.
- Safety: Manageable safety profile. 85% of patients experienced TRAEs, 20% grade 3 or above.
7. Iparomlimab in Advanced Solid Tumors:
- Study Name: Phase 1c study of iparomlimab
- Intervention: Iparomlimab (anti-PD-1 mAb)
- Efficacy: Preliminary clinical activity. ORR: 9.9%, DCR: 36.6%. Median DOR: 10.7 months, time to progression: 1.4 months, PFS: 1.4 months, OS: 9.7 months.
- Safety: Manageable safety profile. 73.2% of patients experienced TRAEs (19.7% grade ≥ 3). TRAEs led to discontinuation in 5.6% of patients.
These studies represent a small sample of the ongoing research in solid tumor treatment. It's important to consult the original publications for complete details and to stay updated on the latest advancements in this field.
Drug used in other indications
The provided text focuses on a phase 1b trial investigating Nadunolimab and Pembrolizumab in patients with metastatic solid tumors who progressed on previous checkpoint inhibitor treatment. While the text mentions this specific trial and discusses other uses of Pembrolizumab, it does not mention any trials exploring Nadunolimab and Pembrolizumab for indications other than solid tumors.
The information available pertains solely to the combined use of Nadunolimab and Pembrolizumab in solid tumors. Specifically, the trial involved 15 patients with stage IV head and neck squamous cell carcinoma, non-small cell lung cancer, or melanoma. Patients received Nadunolimab (5 mg/kg) and a standard dose of Pembrolizumab. The study's primary objective was to assess safety, while secondary objectives included anti-tumor response, pharmacokinetics, and changes in immune mediators.
Key findings of this trial include:
- Adverse Events: Grade 3 or higher adverse events were reported in 7 patients (47%), with one dose-limiting toxicity of febrile neutropenia. The most frequent grade 3 or higher adverse event was dysphagia (two patients).
- Tumor Response: 7 patients (47%) experienced reductions in target lesion size.
- Survival: Median progression-free survival was 3.4 months (95% CI 1.4-8.6). Median overall survival was 19.7 months (95% CI 4.3-28.7), with 67% 1-year survival.
- Biomarkers: Survival was significantly longer in patients with higher baseline tumor infiltration of CD163+ macrophages and natural killer cells and in patients with reduced on-treatment circulating IL-6 levels or neutrophil-to-lymphocyte ratio.
The text concludes that Nadunolimab with Pembrolizumab demonstrated an acceptable safety profile and prolonged disease control in some patients, supporting further development of this combination with checkpoint inhibitors in solid tumors. However, it provides no information about trials for other indications or different intervention models with these two drugs.