Researchers are making strides in lung cancer treatment through innovative drug combinations that boost the effectiveness of immunotherapy, especially in tumors that resist standard therapies. These advancements offer new hope for improved patient outcomes.
ATR Inhibition Enhances Immune Response in Small Cell Lung Cancer
A team from the Icahn School of Medicine at Mount Sinai has shown promising results using a combination of berzosertib (M6620/VX970), an ATR inhibitor, and topotecan for relapsed small cell lung cancer (SCLC). The study, published in Science Advances, highlights that inhibiting ATR activates the cGAS-STING pathway, enhancing the immune system's ability to detect and attack cancer cells. According to Triparna Sen, Ph.D., Associate Professor of Oncological Sciences at Icahn Mount Sinai, this approach makes cancer cells more vulnerable to treatment and boosts the immune system's targeting ability.
SCLC accounts for 10-15% of all lung cancer cases in the United States, with a five-year survival rate of less than 10%. The research suggests that combining ATR inhibitors with anti-PD-L1 antibodies, an immune checkpoint inhibitor, could further improve outcomes. A clinical trial to test these new treatments is planned for 2025.
KRAS and SHP2 Inhibitors Boost Immunotherapy in Lung Cancer
In a separate study, researchers at the Francis Crick Institute, in collaboration with Revolution Medicines, demonstrated that combining KRAS G12C and SHP2 inhibitors with immunotherapy can significantly reduce tumor size and recurrence in mice with lung cancer. The research, published in Nature Communications, indicates that this triple combination sensitizes “immune cold” tumors, which are typically unresponsive to immunotherapy, allowing them to respond to immune checkpoint inhibitors.
Julian Downward, principal group leader at the Crick, noted that the combination led to partial or complete eradication of tumors in mice. The study also found that combining KRAS G12C and SHP2 inhibitors with anti-CTLA-4 blocking antibodies led to a durable response, suggesting additional clinical benefits. However, the researchers cautioned about potential toxicities associated with combination therapies, emphasizing the need for future studies to explore and minimize these effects.
Dual Immunotherapy Benefits NSCLC Patients with Specific Mutations
Researchers from The University of Texas MD Anderson Cancer Center have found that adding the immunotherapy tremelimumab to durvalumab and chemotherapy benefits metastatic non-squamous non-small cell lung cancer (NSCLC) patients with STK11 and/or KEAP1 mutations. The study, published in Nature, identifies KEAP1 and STK11 as potential biomarkers to stratify patients most likely to benefit from the addition of CTLA-4 immune checkpoint inhibitors, including tremelimumab.
The addition of tremelimumab resulted in higher overall response rates (42.9%) compared to patients who received durvalumab plus chemotherapy (30.2%) or chemotherapy alone (28%). Ferdinandos Skoulidis, M.D., Ph.D., associate professor of Thoracic/Head and Neck Medical Oncology, stated that this study provides the strongest evidence to date that patients with STK11 and/or KEAP1-mutated NSCLC may selectively benefit from dual immune checkpoint inhibition.
The ongoing Phase IIIB TRITON trial will prospectively compare dual checkpoint blockade with durvalumab and tremelimumab versus pembrolizumab in combination with chemotherapy in patients with advanced non-squamous NSCLC with STK11, KEAP1 or KRAS alterations.
