Clinical Trial Advances in Cancer Immunotherapy and Targeted Therapies

Multiple clinical trials and treatment approaches are advancing in cancer immunotherapy and targeted therapies across different cancer types. Moderna and Merck are advancing a Phase 2 study testing V940, an mRNA-based cancer vaccine also known as mRNA-4157 or Intismeran Autogene, in combination with pembrolizumab and chemotherapy as first-line treatment for metastatic squamous non-small cell lung cancer.

The Phase 2 study is a randomized, double-blind, placebo-controlled trial evaluating whether adding Moderna's V940 to standard lung cancer therapy improves survival in advanced disease. It targets patients with metastatic squamous non-small cell lung cancer who have not received prior treatment. The trial tests V940 in combination with Merck's checkpoint inhibitor Keytruda (pembrolizumab) and standard chemotherapy drugs carboplatin plus paclitaxel or nab-paclitaxel, with a matching placebo used in the control arm. The study is interventional and randomized with triple blinding, so patients, doctors, and outcome assessors do not know who receives V940.

In biliary tract cancer, first-line treatment is gemcitabine plus cisplatin chemotherapy along with immunotherapy, either durvalumab or pembrolizumab. The TOPAZ-1 trial yielded the first BTC-specific immunotherapy approval, supporting the combination of durvalumab with gemcitabine and cisplatin as the preferred first-line treatment for advanced or metastatic biliary tract cancers. Subsequently, the KEYNOTE-966 trial demonstrated similar positive results when administering the combination of pembrolizumab with gemcitabine and cisplatin.

On failure of first-line therapy in BTC, clinicians typically do not rebiopsy but use initial sequencing results to guide choice of targeted therapies. When employing targeted therapy for second-line treatment, clinicians often perform a solid or liquid biopsy to determine the reason for the failure. With targeted therapies, evolutionary pressure is placed on the cancer to develop resistance mechanisms. Liquid biopsy captures tumor heterogeneity across sites and avoids sampling bias of single lesions, making it more practical and often more informative for resistance mechanisms.

ImmunityBio recently announced the ResQ215B Phase 2 trial, testing a chemotherapy-free, lymphodepletion-free CD19-targeted NK-cell, ANKTIVA, and rituximab regimen in indolent B-cell non-Hodgkin lymphoma. This combination of off-the-shelf cellular therapy with an IL-15 superagonist highlights attempts to differentiate immuno-oncology treatments from conventional CAR-T approaches and checkpoint inhibitor regimens. The ResQ215B Phase 2 launch extends ANKTIVA into a chemotherapy-free, outpatient setting and reinforces the push to position IL-15 biology and off-the-shelf NK cells as an alternative to traditional CAR-T.