NewYork-Presbyterian/Columbia & Cornell Cancer
As the nation’s largest not-for-profit, nonsectarian hospital, NewYork-Presbyterian provides state-of-the-art care at five major centers and is consistently ranked among the country’s best academic medical institutions by U.S. News & World Report. The hospital’s academic affiliations with Weill Cornell Medical College and Columbia University College of Physicians and Surgeons are producing groundbreaking advances in oncology research and patient care.
Established in 2008, the Weill Cornell Cancer Center is a premier center for several oncology specialties, diagnosing and treating over 4000 new patients each year and, in many specialties, conducting more clinical trials than its regional peers. Cancer research at Columbia-Presbyterian Medical Center dates back to the 1911 creation of the Institute of Cancer Research. Armed with the findings of investigators deciphering cancer’s molecular biology, Herbert Irving Comprehensive Cancer Center scientists are intensely involved in the study of cancer epidemiology.
In September 2012 the new joint Cancer Center at Weill Cornell Medical College and NewYork-Presbyterian Hospital was established, bringing together basic, translational, and clinical researchers to operate within a vast, collaborative infrastructure. The new expansive Cancer Center will open its new headquarters in the soon-to-be-completed Belfer Research Building in 2014.
One standout among the prolific research of Columbia/Cornell scientists is their work related to nonchemotherapeutic agents in the fields of thoracic and hematologic oncology.
Balazs Halmos, MD, section chief of Thoracic Oncology at NewYork-Presbyterian Hospital/Columbia University Medical Center, has witnessed dramatic transformations in thoracic oncology from as recently as 5 years ago, when multiple toxic chemotherapy treatments produced only modest benefits. He describes the identification of major genetic mutations in adenocarcinoma as particularly exciting, and cites two FDA-approved nonchemotherapeutic oral agents as especially promising: the EGFR-4 inhibitor erlotinib (Tarceva), approved for treatment of advanced non–small cell lung cancer (NSCLC), and crizotinib (Xalkori), an ALK inhibitor approved for treatment of late-stage ALK-positive lung cancers, and also being investigated for use in other tumor types in which ALK plays an important role.
Balazs Halmos, MD
“Many patients whose tumors harbor one of these abnormalities are reaping the benefits of our enhanced understanding of the molecular underpinnings of lung cancer, with oral targeted agents that, compared to chemotherapy, are less toxic and significantly more efficacious,” said Halmos. “This is producing frequently quite lasting major remissions in roughly two-thirds of patients. Our hope is to cure larger numbers of patients by introducing such agents earlier in the course of the disease.”
Every adenocarcinoma patient at Columbia is now tested for these and other mutations. Those testing positive can be treated with an approved agent or enrolled in clinical trials, with patient samples used as laboratory models for the next wave of drug development. Halmos uses ALK to illustrate the importance of such screening. “While only 5% of patients with NSCLC have the ALK mutation targeted by Xalkori, the disease is so common that this percentage represents approximately 9000 individuals annually.” With mutations in other key genes being rapidly identified, it is hoped that even more patients will benefit.
Halmos and colleagues were among those who made key observations on these and other genetic abnormalities; in particular, through research on the mechanisms of the acquired resistance to EGFR and ALK inhibitors. The team also participates in multiple trials of such targeted agents, including the key studies that led to Xalkori’s approval.
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.”
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.
GS-1101 is a highly selective inhibitor of the delta isoform of PI3 kinase, which acts as a “central integration point for signaling from multiple cell surface receptors known to promote malignant B-cell proliferation and survival.”4 “While the PI3 kinase enzyme’s critical importance is evidenced by its presence in every cell in the body, the delta isoform has been shown to be uniquely utilized by hematopoietic cells,” Furman explained. “GS-1101’s ability to inhibit PI3 kinase has been seen in vitro, but the extent of its potential role in the treatment of B-cell malignancies did not come to light until early-phase clinical trials. Given the critical nature of cell–cell interactions in promoting cell survival, including CLL and lymphomas, enzymes like PI3 kinase, which channel several different surface-derived signals to the nucleus, are often difficult to study ex vivo,” Furman noted.
Ibrutinib and GS-1101 both performed remarkably well and without toxicities in phase I trials, and 200 to 250 patients nationwide have now been exposed to the agents in phase II trials. Weill Cornell investigators are currently involved in the pivotal studies of both agents that will hopefully lead to their approval within 18 months.
Furman, who has had patients on the drugs continuously for 3 years without long-term sequelae, noted that both are well tolerated. “Mild diarrhea develops in about 10% to 15% of those taking ibrutinib, and can be controlled with conservative measures. About 2% of GS-1101–treated patients require oral steroids and discontinuation of the GS-1101 related to an inflammatory colitis that develops approximately 15 to 18 months into treatment, and approximately 10% experience an asymptomatic transaminitis during weeks 4 to 5. The transaminitis resolves with GS-1101 discontinuation, and patients can often be treated through the transaminitis or successfully rechallenged with a lower dose that is slowly titrated upward.”
Questions still remain. “We don’t yet know if these drugs will need to be taken lifelong,” said Furman. “Most of these patients have had refractory CLL and lymphomas and have now achieved excellent remissions with no adverse effects. I would be hard-pressed to want to stop their treatment.”
Citing the toxicities associated with conventional chemotherapy as one of the biggest obstacles to transforming CLL and low-grade lymphomas into truly chronic diseases, Furman noted that “as patients survive longer with novel therapies, and are exposed to multiple rounds of chemotherapy, bone marrow suffers repeated injury to the point of developing myelodysplastic syndrome and subsequent acute myeloid leukemia, which is what causes their deaths. This is why these nonchemotherapeutic options are so critical.”
Furman’s hope is that, ultimately, his patients won’t require chemotherapy, and will simply take a daily pill. “I couldn’t imagine practicing at any other time. My clinic is becoming a place where patients come and pick up brown bags of medications, and then go home to lead their lives.”