Chapter 88
Cancer — 15
In contrast, mutation-directed treatment was successful in advanced breast cancer in women who had “HER2-low” tumors. A person may have too little of the HER2 growth factor and develop HER2-low cancer (about 55% of breast cancer patients), or a person may have too much of this particular growth factor and develop HER2-positive cancers (about 17% of breast cancer patients). HER2-positive breast cancer already had effective treatments, but HER2-low has been a challenging puzzle. A randomized trial of the drugs trastuzumab deruxtecan versus untargeted therapy (T-Dxd) in more than 550 HER2-low patients, who had failed previous therapy, led to significant improvement of survival, and progression-free survival.
This is noteworthy since there was an average seven-month improved survival, which contrasts to the expectation of only weeks or no benefit in survival for such patients. T-Dxd is the prototypic antibody-drug conjugate, essentially the drug Herceptin linked to a chemotherapy drug so the latter can achieve high concentration in the tumor, less release throughout the body. That enhances efficacy while also reducing side effects. How could this marvelous success have been achieved?
The drug is called a conjugated (two molecules joined together) antibody because it uses an immunotherapy (trastuzumab) to attach to the cancer cell and deliver the deruxtecan, chemotherapy drug, to get into the cell to destroy it. These “weaponized antibodies” are having unprecedented success for challenging tumor types, such as using vedotin for bladder cancer, or tebentafusptebn for malignant melanoma, EGFR-HER3 for several advanced solid tumors. Over twenty such “biological missiles” have been approved by the FDA, and many more are in ongoing clinical trials.
Targeting tumor protein P53 (TP53), the most common cancer driver mutation, but without an effective treatment, may even be possible using a conjugate strategy. An antibody-drug conjugate targeting a blood stem cell marker is an exciting new approach to treat blood cancers and autoimmune diseases. This class of drugs is associated with some unique toxicities of the lung, eye, and skin that must be carefully monitored.
The antibody-drug conjugates build on our current immunotherapies that power up our immune system to fight cancer by releasing the brakes of T cell activation, a process that can be suppressed by cancer cells. T cell activation is a multipronged body defense process whereby T cells spot intruders (such as a cancer cell). A molecular signal calls in the troops for more T cells, which multiply by the millions and differentiate into other types of immune cells to eliminate the intruder. T cells and their helper cells then release proteins called cytokines, which can kill cancer cells.
The mainstay of our cancer-directed immunotherapies are checkpoint inhibitors, blocking the part of our immune system that constrains the T cell response. A more robust, unbridled activation of T cells results. The list of checkpoint inhibitors includes pembrolizumab (Keytruda), nivolumab (Opdivo), and cemiplimab (Libtayo) that target programmed cell death protein 1 (PD-1); atezolizumab (Tecentriq), durvalumab (Imfinzi), and avelumab (Bavencio) that target programmed cell death ligand 1 (PD-L1); Keytruda, Opdivo, and Loqtorzi that block the interaction between PD-1 and PL-D1; Ipilimumab (Yervoy) that blocks CTLA-4; and Opdualag (a LAG-3 checkpoint inhibitor, retalimab-rmbw, combined with nivolumab). One trial of PD-1 blockade for advanced colorectal cancer is notable. All among a small group of patients with mutations in genes that correct errors in DNA replication, known as mismatch repair-deficient, had a pronounced clinical response with no tumor detected by follow-up imaging. However, this result is an exception—most checkpoint inhibitor interventions only yield short-term success. There is also a group of antibodies called bispecific T cell engagers (BiTEs), which have a linker, like the antibody-conjugate drugs, to bridge tumor and T cell recognition, power up the immune response, and kill cancer cells. Several BiTEs are now approved for blood cancers, and more are in clinical trials.