Articles related to TARGETED THERAPIES

Targeted therapy gene mutations may: (a) encode a protein that can be targeted in a manner distinct from the WT protein; (b) cause abnormal activation of a protein that is druggable but for which mutant-specific targeting has not been achieved; or (c) create novel molecular dependencies that are druggable. This article describe key examples of genetic drivers and associated modes of druggability, considers the clinical and research challenges in the field, and discusses new approaches to maximizing therapeutic benefit of targeted therapies.

The phase 3 KEYNOTE-048 trial compares pembrolizumab with or without concurrent chemotherapy to cetuximab-chemotherapy in patients with recurrent or metastatic head and neck SCC. Patients were evaluated in subgroups based on PD-L1 expression. In median survival, pembrolizumab + chemotherapy outperformed cetuximab + chemotherapy in all patient subgroups regardless of PD-L1 expression. In the PD-L1 CPS 1-19 subgroup, pembrolizumab alone slightly outperformed cetuximab + chemotherapy. In the PD-L1 CPS < 1 subgroup median survival was significantly lower with pembrolizumab alone.

Mirvetuximab soravtansine is an antibody-drug conjugate that consists of an FRα-binding antibody, cleavable linker, and maytansinoid DM4, which is a potent tubulin-targeting agent. It was tested in a single-arm phase 3 trial that included 106 patients with platinum-resistant, high-grade serous epithelial ovarian, fallopian tube, or primary peritoneal cancers with high FRα expression. The investigator-assessed ORR was nearly triple the benchmark set in prior studies of less heavily pretreated platinum-resistant ovarian cancer populations. The ORR was similar regardless of the number of prior lines of therapy or prior PARP inhibitor exposure. The rapid and durable response seen with mirvetuximab in patients with FRα-positive, platinum-resistant ovarian cancer may position it to become a practice-changing, biomarker-driven standard of care treatment option.

Researchers reported the finding—the longest known CLL remission after CAR T-cell therapy—in Nature. The patients received an infusion of genetically engineered autologous T cells as part of a phase 1 clinical trial in 2010.

Recent studies identify DNA damage repair (DDR) genes as a new class of endocrine therapy resistance driver that contributes to poor survival among ER+ breast cancer patients. This study reveals differences in DDR regulation in Black women that may in part contribute to the higher breast cancer mortality in Black women vs. other populations. Based on their findings, the authors recommend more effort to refine biomarker profiles to ensure precision medicine for underserved populations.

In a randomized clinical trial of 128 patients with refractory mCRC, the addition of the PD-L1 inhibitor atezolizumab to capecitabine and bevacizumab therapy resulted in marginally longer PFS vs the placebo comparator arm. However, the median improvement — 4.4 vs 3.6 months – was deemed not clinically relevant.