VM Oncology Pembrolizumab Phase 1/2 (NCT03556228)

In a phase 1 trial of VMD-928, an oral allosteric TrkA inhibitor, common adverse events in 20 non-biomarker-selected people with advanced solid tumors included dark stool (35%), elevated liver enzymes (25%, mainly at 2400 mg/day), and fatigue, nausea or vomiting, and decreased appetite (20% each). One dose-limiting toxicity occurred at 2400 mg/day, involving elevated bilirubin, AST, and ALT in a person at that level. The recommended phase 2 dose of 1200 mg/day (600 mg twice daily) showed no dose-limiting toxicities, with mainly gastrointestinal side effects reported. Similar Trk inhibitors have generally been well tolerated without serious side effects. VMD-928 remains investigational and unapproved by the FDA.

Mesothelioma is a rare cancer caused by asbestos exposure, primarily affecting the mesothelium lining the lungs (pleura), abdomen (peritoneum), heart (pericardium), or testes. Asbestos fibers inhaled or ingested lodge in these tissues, causing chronic inflammation and DNA mutations that lead to cancer over decades. Pleural mesothelioma accounts for 80% of cases, peritoneal for 20%, and pericardial or testicular types for less than 1%.

Immunotherapy has shown the strongest clinical outcomes in melanoma, non-small cell lung cancer, colorectal cancer with microsatellite instability (MSI-H), and certain blood cancers. In melanoma, 20-40% of people with advanced disease achieve durable long-term responses, while CAR T-cell therapy has achieved remission in up to 90% of children and young adults with specific leukemias. For colorectal cancer with MSI-H mutations, pembrolizumab produced 98% one-year survival and 84% three-year survival rates in clinical trials. Checkpoint inhibitors have also extended survival in bladder cancer, gastric cancer, and cervical cancer, with over 40 immunotherapy drugs now approved across more than 30 cancer types. Response rates vary significantly by cancer type and individual tumor characteristics, making biomarker testing important for treatment selection.

People with asbestos-related cancers, such as mesothelioma or lung cancer, receive treatments including chemotherapy with drugs like pemetrexed plus cisplatin or carboplatin, immunotherapy, surgery, and radiation. Chemotherapy is the most common approach, used in 32% of mesothelioma cases often combined with immunotherapy, which is FDA-approved as first-line for pleural mesothelioma and extends median survival to about 18 months. For asbestosis, a non-cancerous condition, management focuses on avoiding further exposure, quitting smoking, and symptom relief with oxygen or medications, as no reversal is possible. Clinical trials testing new combinations are ongoing and listed on ClinicalTrials.gov.

Pembrolizumab (Keytruda) is not classified as chemotherapy. It is an immunotherapy drug known as an immune checkpoint inhibitor that targets the PD‑1 pathway to help the immune system recognize and attack cancer cells. Unlike traditional chemotherapy, which directly kills rapidly dividing cells, pembrolizumab modulates immune responses and can be combined with chemotherapy in some cancers, including malignant pleural mesothelioma. Clinical trials report improved overall survival in several metastatic cancers when pembrolizumab is used alone or with chemotherapy, although it can increase immune‑related side effects.

Clinical trials that inform real‑world practice typically cap pembrolizumab at about 2 years of therapy. On the standard 3‑week schedule, this equals 35 treatment cycles, as seen in multiple KEYNOTE studies in advanced non small cell lung cancer. For people switched to the 6‑week schedule, 2 years of treatment generally corresponds to 17 or 18 infusions, since each 6‑week dose covers roughly two 3‑week cycles. Research following people for 5 years suggests that completing these 35 cycles can lead to durable responses in a substantial share of participants, with some studies reporting about 69% alive at long‑term follow‑up. Observational data in lung cancer also indicate that stopping pembrolizumab at 2 years (around 35 cycles) may offer similar overall survival compared with continuing beyond that point.

Clinical trials that led to KEYTRUDA approval generally capped treatment at about 2 years (often 35 cycles), so most long term safety and benefit data come from this timeframe. In practice, some people with mesothelioma or other cancers do continue KEYTRUDA beyond 2 years, particularly in regions where regulators allow it and when their cancer is still responding without severe toxicity. Large studies in cancers such as non small cell lung cancer report that stopping at 2 years did not worsen overall survival compared with continuing longer, which has fueled interest in fixed duration strategies. Researchers also note that longer treatment can raise the risk of chronic immune related side effects and financial burden, so duration is often individualized based on response, side effects, and evolving evidence.