Resistance Remains Problematic
Despite this promise, cancer cells ultimately “outsmart” new therapies, developing new mutations of the same gene or employing bypass mechanisms to activate another gene as a key driver of malignancy. NSCLC’s activating mutations in EGFR frequently respond to EGFR-targeted tyrosine kinase inhibitors (TKIs), but those responses aren’t durable. Investigators, including Halmos’s team, have identified secondary mutations in EGFR in about 50% of resistant tumors. Most recently, increased ALK expression was identified in approximately 20% of EGFR-mutant lung cancers from patients with acquired TKI resistance.1
Similarly, most ALK-positive NSCLCs are responsive to treatment with ALK TKIs, but patients almost always experience resistance-induced relapse, typically within 1 year.2
Halmos notes that future success depends upon appropriate combination therapies targeting common pathways of resistance. The Columbia team actively participates in studies in this area, such as a recent trial of combined EGFR- and MET-inhibitors, and an upcoming study of ALK and heat shock protein 90 inhibitors, among others.
Mari Lynne Silverberg,
BSN, RN, OCN®, MPA
Patient Care Director for NewYork-Presbyterian Hospital’s Infusion Center Mari Lynne Silverberg, BSN, RN, OCN®, MPA, notes that agents like Tarceva and Xalkori add a new dimension to patient care. “We’re watching for how patients react, and how these cutting-edge oral agents might interact with conventional IV chemotherapy drugs, exacerbate existing adverse reactions, or cause new ones,” she said.
While formal in-service training is provided whenever a new agent will be administered, keeping the infusion staff informed about treatments given outside the center requires networking with pharmacists, physicians, practice nurses, and others on a “need-to-know” basis. Tarceva’s pharmaceutical medical liaison provided on-site informal education, but Silverberg noted that much of their education is accomplished “on the job.”
To date, a few infusion center patients being treated with Tarceva have developed a mild form of a rash that is more psychologically upsetting than functionally debilitating. The rash develops about 1 to 2 weeks after treatment initiation in about half of those taking the oral agent and usually resembles severe acne but also can look like a bad sunburn. It usually appears on the face but sometimes only on the trunk, can be intermittent or constant, and can range from mild to severe. It also can be associated with intense itching and typically changes in character throughout treatment (eg, from pustual to nonpustual). While the rash resembles acne, drying medications are not recommended; patients are typically encouraged to use good hygiene, stay hydrated, use gentle cleansers, and avoid sun exposure. Topical steroids can sometimes provide temporary relief.
“Patients often need help in dealing with a rash they may view as disfiguring,” said Silverberg, “and support also is needed for those who don’t develop the rash and may view this as a sign that the drug isn’t working.”
Ibrutinib and GS-1101: New Hope for CLL and Lymphoma Patients
Despite the complexities related to the introduction of new treatments, Silverberg views the advent of oral nonchemotherapeutic agents as especially promising. In agreement is Richard R. Furman, MD, director of Weill Cornell’s Chronic Lymphocytic Leukemia (CLL) Research Center and a senior member of the Center for Lymphoma and Myeloma, who notes that such agents are proving to be a huge boon to CLL and lymphoma patients.
Weill Cornell is one of a handful of centers that participated in the phase I trials of ibrutinib and GS-1101, two oral kinase inhibitors showing promise for CLL and lymphoma. Both molecules inhibit pathways involved in B-cell receptor signaling, inducing a rapid and dramatic shrinkage of lymphadenopathy regardless of prognostic markers, said Furman. While interest in the drugs was originally focused on CLL, both have been shown to be efficacious in low-grade lymphomas.
Ibrutinib is a highly selective inhibitor of Bruton tyrosine kinase (Btk),3
which is required not only for B-cell antigen receptor signaling, but is now known to play a role in cell-stromal interactions. Btk is involved in conduction signals from the cell surface deep into cell interiors, regulating vital processes. “We now believe that Btk is one of the key pathways in the pathogenesis of CLL and other low-grade B-cell lymphomas,” said Furman.